Finally free of Smallville's expectations, Clark, and the metahumans of her hometown, Lana believed she could finally start to build her own life. In Paris, she met Jason Teague, and started a relationship with him. While taking a brass rubbing of the ancient tomb of Countess Margaret Isobel Thoreaux, Lana passed out and was imprinted with a weird symbol. After discovering that the symbol was similar to the ones in the Kawatche Caves, Lana had to return to Smallville to learn more about the mysterious tattoo on her back. As soon as she arrived in town, she learned of the death of Chloe and went to visit her at the cemetery, meeting Lois Lane in the process. After seeing Clark again, the two talked about her return, but she refused to tell him the real reason why she had returned. After talking with Lex, Lana managed to live in the Talon apartment and soon was joined by Jason who followed her from Paris to be with her. Lana and Jason continued their relationship in Smallville, keeping it a secret because of Jason's job as the high school assistant football coach. However, when Lionel Luthor, in Clark's body, walked in on Lana and Jason making out, Lana later confronted him and Lionel (still in Clark's form) kissed her: she slapped him and stormed off. This caused her relationship with Clark to crumble especially after Jason was fired due to being accused of having a relationship with Lana. Unable to find an answer to her tattoo, Lana researched Isobel and learned that the Countess was her ancestor and that she was burned at the stake as a witch. After she touched Isobel's spell book, Lana was possessed by the Countess. As Isobel, she placed a spell on Lois Lane and Chloe Sullivan, causing them be possessed by her two cohorts. After Clark destroyed the spell book, Lana, Chloe, and Lois returned to normal and Lana then learned that it wasn't Clark who informed the school that Jason was dating a student: it was Lex. "Oh great, possessed by an evil slut.".

After being possessed by her ancestor, Lana started to have dreams where she witnesses the execution of Isobel Thoreaux and also of a woman yelling at Isobel angrily. Lana was shocked to learn that the woman of the dream looked immensely like Jason's mom and then began to suspect the real reasons that Jason had begun to date her. Although her ​​relationship with Jason was stable, her past with Clark still followed her and this caused Jason to begin to doubt her. Lana tried to give her virginity to Jason as a show of loyalty, but he refused. Later on, Lana was furious that Jason accepted Lex's job offer, but Jason tells her he would use this to get to more information about Lex as well as for his and Lana's research on the Countess. However, when Lex told Lana that Jason already knew everything about Isobel before they met, Lana had to reevaluate how well she knew Jason. When Lionel informed Lana that Jason and Lex were in China together searching for one of the Stones of Power, and that Duchess Gertrude (Jason's ancestor) had been obsessed with finding the stones as well, he made arrangements for Lana to go to China on the LuthorCorp jet. Clark offered to go with her and after arriving, went to a temple where the Crystal of Air was located. Lana got captured and was taken to Jason and Lex only to be possessed again by Isobel. After having fought Clark for possession of the stone, Lana reverted to her true self and Jason managed to sneak the Crystal of Air to Smallville without Clark and Lex noticing. Lana then decided to hide the stone from everyone else, including Jason and pretend that a thief stole the stone. By this time, Lana felt quite confused and shocked to learn that Lex had secret feelings for her as he kisses her while being split in two. Also, she started to get closer to Clark again after feeling that he was the only one she could trust. This was discovered by Jason at the prom dance and their relationship comes to an end. As the year ended, Lana's feelings for Clark returned. Lana and Clark discovered an abandoned baby in the cornfield and took him back to the Kent Farm, where they bonded over the foundling, whom Clark named "Evan." After Evan died, they reminisced about their time with him. Then Lana started to feel that she could be with Clark after all. When she was attacked by Genevieve Teague, who figured out that Lana had one of the Stones of Power. Isobel once again possessed Lana, and stabbed and killed Genevieve with the Crystal of Air. After Isobel went dormant within her, Lana was given refuge by Lex. When another meteor shower was predicted to hit Smallville, Lex helped Lana leave Smallville. Before leaving, Lana gave the Crystal of Air to Clark, feeling that only he would know what to do with it. The two confessed their love to each other and went their separate ways. Lana tried to send a message to Chloe, but was stopped by Lex, because he didn't want anyone to know what was happening. Lex got Lana into a helicopter: as they took off, Lana and the pilot dodged the falling meteors. However, one struck the tail of the helicopter and they plummeted to the ground. Though badly injured, Lana managed to survive the crash and pulled clear of the helicopter. She dragged herself to a nearby crater and pulled herself up to its edge, spotting the Black Ship, which began to open.

Lana realized that Lex was possessed by General Zod, who took her captive and brought her to the Luthor Mansion. Zod told her that the reason he needed her was because he wanted to sire an heir with her. When Lana declined, Zod impaled her hand against a wall with a fire poker. Lana managed to get free and went to the Kents for help: she was told by Martha that Lex had to die. Lana decided to take the Kryptonian dagger and kill Lex in order to stop Zod. When she got close enough, Lana tried to stab Zod with the dagger but he took it from her and broke it. As Zod began to choke her, Clark returned: Zod released Lana to deal with Kal-El and was eventually defeated by Clark. Lex denied having any memory of what happened while he was possessed by Zod and with the dormitories of the University closed after the events of Dark Thursday, Lana moved in with Lex at the mansion but was very disturbed with how he had a surveillance camera in her room, watching her. After a slight discussion, Lex removed the cameras from her room but told Lana that the cameras are his way of life. She was even more concerned about her relationship with Lex after being catalogued as "the next Lex girl" and wondered what happens when Lex actually gets what he can't have, so she discussed it with Chloe. Chloe advised Lana to stop living in the past and move on with her life. Ultimately, Lana decided to pursue a relationship with Lex, and the two became intimate. Lex wanted to test Lana's loyalty and enlisted Lionel's help to prove it and told him to encourage Lana to destroy the Kryptonian black box that Zod tried to use to transform Earth into a new Krypton. Lana blackmailed Dr. Groll into getting rid of the device and when it was found out by Lex, he was impressed by Lana´s determination. Lex and Lana both wanted to use the device to prevent any more Kryptonians from taking over the world. Lana continued her relationship with Lex without many conflicts, but after their relationship was strained when they fight over the Kryptonian black box, Lana gave Lex an ultimatum: the box or her. Since the box dissolved after the Zoner Baern absorbed its data, Lex said that he was going to choose her. Lana's doubts about Lex began to increase and then she went to see Chloe for lunch, but had a fainting spell. Lana went to her doctor to get a checkup and discovered that she was pregnant: as well as later admitted it to Chloe. Lana kept her pregnancy in secret from Lex for days until she finally told him after thinking that she had lost Lex forever due to a meteor freak. Later, Lex proposed marriage to Lana, much to her surprise. Lana did not gave an answer to Lex's proposal quickly and finally confessed to Chloe she had reservations about marrying Lex due to her lingering feelings for Clark. After gossip columnist Linda Lake published the exact conversation in an article, Lana went to Chloe to confront her but realized that it was Linda who was responsible. Later, Lana went to Clark to talk to him and asked him to place his trust in her just once and tell her the secret that had been between them for so long. Clark claimed that it didn't matter and revealed that he knew she was pregnant, and that everything had now changed. He then told her that he hoped Lex made her very happy. Lana traveled back to the Luthor Mansion and accepted Lex's proposal. At her engagement party, Clark and Lois, both infected with red kryptonite, broke into the mansion and let everyone know that Lana was carrying Lex's child. After Clark kidnapped Lana and forced her to admit that she still loved him, Lex came there in time to rescue Lana from him. As Clark was about to kill Lex, Lana saw Clark get stabbed by a chisel, but she saw it was only dented. She kept it and hoped that it would bring her closer to Clark's secret. As Lana started to grow closer to Clark's secret, she was shocked to learn that someone was spying on her and indignantly decided to seek refuge in her friends since Lex was out of town. Lana decided to stay at Chloe's apartment and while there attempted to look through Chloe's computer to discover more about Clark but it was password protected. After her stalker found her again, Lana stayed at the Kent Farm in Clark's bedroom where she saw that Clark kept her necklace but that it now looked different. Her suspicions towards Clark were increased when he mysteriously rescued her from her stalker. Lana came to the conclusion that Clark was probably being infected by the meteorite and after a meteor freak was abducted during her bachelorette party, she went to see Chloe to ask her why she went outside last night. Chloe told her about what Tobias Rice, the only suspect in the kidnapping, could do. She also asked Lex if he knew him, and he lied to her, saying that he didn't. Lana went to see Tobias and told him that she knows that Clark is infected as well and offered to pay for his surgery in the hopes of protecting Clark's secret from being revealed. Tobias told her that Clark was normal, confusing Lana even more. However, the day of her wedding, Lana resolved to find out the truth about Clark and locked Chloe in the wine cellar, knowing she would call Clark to rescue her. Lana witnessed Clark's superpowers and heard him and Chloe talking about how he was still in love with Lana. Finally realizing why Clark had been lying to her all these years, Lana decided that she could not go through with the wedding and tried to write Lex a letter to cancel the wedding. However, Lionel discovered that she knew Clark's secret and told her that if she did not marry Lex, he would kill Clark. Trapped, Lana married Lex after all. One week later, she told Lex that she didn't feel well enough to go on their honeymoon, so they canceled the trip. After Lana collapsed in pain and passed out, Lex was forced to tell her that she had suffered complications and miscarried the baby. Lana was heartbroken by this revelation and began to cry bitterly. After she was attacked and knocked unconscious by a mind controlled metahuman, she was rescued by Clark and Chloe. She woke up in Smallville Medical Center, were after performing thorough tests in light of her recent "miscarriage," a doctor informed her that she was never pregnant and accused her of taking synthetic hormones to simulate a pregnancy and trick Lex into marrying her. Having seen sonograms, she protested and was left in a state of shock and bewilderment. After this discovery, Lana began to harbor a deep, dark, secret hatred for Lex and Lionel. When Lex was trapped underground in an explosion she simply hoped he'd die. Demanding answers, Lana blocked Lionel's IV drip delivering pain medicine after he was wounded in the explosion and Lionel revealed that he blackmailed her to protect Clark. Lana then recovered a briefcase the police found in Lex's car and shot the locks off. Inside, she found a disc labeled Project Ares, along with floor plans of the tunnels in which Lex was trapped. After learning that Clark was trapped inside the tunnels too, she was forced to reveal the exit. Lana visited Lionel again and demanded to know what Lionel knew, threatening to tell Martha about him using Clark as a bargaining chip. Lionel revealed to Lana the truth and then the two begin to work together to stop Lex and save Clark. However, Lana was shot at the Daily Planet after seeing Lionel about Project Ares and this began to attract the attention of Chloe who demanded the truth about her marriage to Lex. Lana told her that she married him to protect Clark. Lana maintained the facade of the loving wife and in dialogue loaded with double and secret meanings, Lana told Lex that if someone lied to her like that they would lose her love forever. Even as they hugged, over Lex's shoulder, Lana revealed her deep hatred for Lex. Finally, Lana overheard a meeting with Lex and Senator Burke. She later told Clark about it and was warned by Lex to never betray him again or he wouldn't know what he would do. Lana met Clark at his barn and told him she was leaving Lex, and Smallville, to escape. Clark told her his secret in an attempt to get her to stay, but she only kissed him and left after telling him, "You're still the same Clark Kent to me." At the mansion, Lana confronted Lex about the fake pregnancy, telling him that Clark meant more to her than Lex ever would, and told him their marriage was over. After Lex hit her, she left saying, "That's the last time you'll ever touch me." Lana was next seen running to her car while telling Lionel on her cell phone that she was leaving. Lionel watched in horror as her car exploded, with Lana seemingly inside. Unbeknownst to anyone else, Lana found out that Lex had created a clone (model 503) of her in a 33.1 facility at the Reeves Dam as well as, in order to escape from both Luthors, decided to fake her death and worked out a complicated plan. She provoked the discussion with Lex so this might give her the perfect alibi and made Lionel believe that she really was leaving Smallville to avoid suspicion and to have a potential witness for everything that would happen. She put the Model 503 in her car and then blew it up in front of Lionel, making it appear that Lex had murdered her.

Shortly after her reported death, Lana was seen alive in hiding in Shanghai, China wearing a blonde wig for weeks. No one was aware of her faked death until Lex found her in Shanghai. She left her clone (Model 503) that Lex created in her car so that when it blew up, they found her DNA. While explaining all of this, Lana held Lex at gunpoint but she was unable to kill him despite his actions. He told her she could return to Smallville and that he would take care of everything for her. Lana took Lex up on his offer and returned to Smallville, meeting Clark in his barn. He was shocked to see her alive but also delighted at the same time. He invited Lana to stay with him at the farm, until her name could be cleared. Lana called Lex over to discuss her situation, confirming that she accepted Lex's offer. Lana was later seen with Clark at a public carnival, suggesting that her name has been cleared. While living with Clark, Lana met Clark´s Kryptonian cousin Kara and the Martian Manhunter. Clark found out through Lex that Lana had stolen ten million dollars from him and when he confronted Lana about the money, Lana explained that it was another one of Lex's ways to split them up and that the money was a divorce settlement, which was the truth. She assured Clark that she would never keep secrets from him. Then she went to her own secret hideaway where she had numerous security screens watching over the Luthor Mansion and Lex himself. Lana was increasingly consumed with vengeful feelings towards Lex and Lionel Luthor, which she hid from Clark. It was revealed that she was responsible for having Lionel being held prisoner by a crazy woman in a log cabin and once Lionel got free, he confronted Lana at the Kent Farm and warned her not to continue her descent to the dark side or something bad would happen to her. When Lana told Clark that she doesn't want to hold him back when the world needs him more than her, Clark assured Lana that he is happy with her and she doesn't need to worry and that gave Lana a green light to continue in her affairs. When Chloe found out about Lana's Isis Foundation, designed to help the meteor-infected, Lana asked Chloe to keep the Foundation a secret - especially from Clark. Chloe agreed but sensed that there was something Lana was hiding. Lana said that it was Chloe's imagination and that there was no secret. Despite all this, Lana managed to fool Clark and made him try to get their relationship on track by being more honest with each other. During a romantic afternoon, they were struck by lightning and Lana received some of Clark's powers. Her new abilities amplifying her anger, Lana wanted vengeance and to make Lex pay for his crimes. While trying to cure her, Clark discovered the Isis Foundation and found out that she had been watching Lex for months. Lana went to confront Lex. He remarked that Lana was still in love with him and kissed her. Lana continued her assault on him and was only stopped from killing Lex by Clark himself. He overpowered her and used a live wire to take the powers from her. After that, Lana chose to face the consequences of her actions although Clark blamed her behavior on himself. She informed him that she made her own choices and claimed that she kidnapped Lionel because she was protecting Clark. She was not remorseful, saying that she just needed to know that he would love her no matter what. Chloe also confronted her as well and informed her that she would not let Lana bring Clark down with her. When Lana met Clark's biological mother, Lara, she agreed to keep Lara company while Clark met up with Kara. Lara told Lana that she could see the darkness Lana was battling, but their conversation was cut short when Zor-El stormed in to take Lara. Lana tried to protect her but Zor-EL flung Lana in the air, injuring her. Later Lana told Clark that she doesn't know if she deserves him after all she's done, but Clark assured her that it is okay to make mistakes. After two weeks of being missing after he went to plead with Jor-El to find Kara, Clark seemingly returned home and declared that Kara was gone forever. Lana told him that she was done spying on Lex but Clark then asked to see what she had discovered. As Lana restored her surveillance room in the Isis Foundation, they investigated something Lex was working on called Project Scion. Lana showed Clark a woman who was found suffering from toxic levels of metal poisoning and Clark discovered that Brainiac was alive. After rescuing Chloe and Jimmy, it was revealed that "Clark" was, in fact, the escaped Zoner Bizarro. For the next two weeks, "Clark" and Lana seemingly reconnected. He declared that they could run away together from Smallville and Lana agreed. When the real Clark returned, Lana could not believe that she had been living with an impostor for weeks. Clark was dismayed that Lana had been completely fooled and despite this Lana tried to atone by helping Clark defeat Bizarro. She admitted that Bizarro made her feel more loved and happier than she ever had been. This caused Clark and Lana's relationship to be strained to the brink. After Lionel approached Lana asking for surveillance on Lex, blackmailing her in the process, Lana decided to tell Clark, who was angry that Lana was only telling the truth because she was being threatened. They argued over what one expects of the other and Lana finally decided to stay with Chloe for a few days, but Clark confessed that he wasn't ready to give up on them. After Lex was shot in the head, Lana provided Clark and Chloe information about Project Intercept with the resources she had at the Isis Foundation so that they could find Kara. Then, Lana and Clark returned to live happily together without secrets. When Kara returned with amnesia, Lana and Lionel convinced Clark not to tell her the truth about her origins. However Kara confronted Lana and demanded the truth. When Lana didn't tell her anything, Kara was driven to Lex, believing that Clark and Lana did not have her best interests at heart and moved in with him. Finally when Clark decided to go to the Fortress to ask Jor-El what to do, he disappeared and Lana called Chloe to help find him. They discovered a Kryptonite dart in the barn and confronted Lionel. Lionel threw suspicion onto Lex and Chloe and Lana quickly believed him, saying that she would kill Lex if he hurt Clark. However, Chloe found evidence that Lionel was in fact responsible. Lana told Chloe about secret passages into the mansion and they set out together to rescue Kara from the mansion so she could rescue Clark. With Brainiac's return, Kara tried to teach Clark to fly, so he sent Lana to Isis. There, Brainiac attacked her, leaving her in a catatonic state: allowing Brainiac full control over her body, and only reversible by him. He sent her home to deliver a message to Clark and Kara. Brainiac told them that Lana was in excruciating pain and aware of her surroundings, but was unable to control her own body. Although Kara chose to follow Brainiac's orders, he does not release Lana and she was somewhat mobile but remained relatively unresponsive to outside stimuli. After Brainiac and Kara's departure, Clark took her to an asylum, but no sort of treatment was able to help her. Even after Clark and Kara defeated Brainiac, her condition continued to deteriorate. Lex revealed that he had his best doctors evaluate her, but they too were unsuccessful at treatment. When Clark finally destroyed Brainiac, Lana awoke from her catatonic state, completely recovered. She made Clark a video and left it at the hospital for him to find. Lana told Clark that the world needed him more than she did and that they were not meant to be together. She continued to say they were only fooling themselves. She told Clark that she was leaving and he should not follow her. She let him know that she still loved him, more than he would ever know.