Three months later. Lois Lane, the second cousin of Chloe Sullivan, arrives in Smallville trying to find the missing Clark Kent to help her to find Chloe's murderer. After being struck by a mysterious ray, she loses control of her car, and finds Clark naked with amnesia in a cornfield. She brings him to Smallville Medical Center, where Martha is with Jonathan Kent, who has been in an irreversible coma. Martha brings Clark back to the farm, expecting him to retrieve his memory. However, Clark is completely dehumanized, having been taken over by his alter-ego Kal-El, whose mission is to find three Kryptonian crystals to assemble into one. Meanwhile in Paris, Lana Lang has an American boyfriend, a young man named Jason Teague, and is having a good time with him, until things take a turn when she gets hit with a mysterious spiritual force containing the spirit of a long-dead witch. Elsewhere, Lex is struggling to recover from being poisoned as he travels to bring an ancient object retrieved from an excavation in Egypt which Clark/Kal-El is also after and uses his flying abilities to steal the crystal... in midair. Also, Lois visits the imprisoned Lionel to talk with him about Chloe, while Martha has a meeting with an associate of Virgil Swan's, named Bridget Crosby, who gives her a new type of kryptonite to combat Clark/Kal-El.

The mystery surrounding Chloe's death deepens as Clark and Lois investigate, discovering that Lex Luthor and Lois' abrasive and militarist father, U.S. Army General Sam Lane, are somehow involved. Meanwhile, Lana returns to Smallville after finding out that the symbol that appeared on her back in Paris is also on the cave wall. In prison, Lionel Luthor prepares for his murder trial and sends out a liquid-metal assassin to keep Clark and Lois from investigating Chloe's 'death'.

Without the approval of his father, Clark kicks off senior year by trying out for the Smallville High Football Team, who are now coached by Lana's new boyfriend, Jason Teague. Former acne-ridden nerd Abigail Fine returns from the summer looking beautiful after some Kryptonite powered plastic surgery that spells trouble for Lana and a former tormentor when Abigail discovers that the side affect makes people insane and delusional to anyone she physically kisses. When Lois investigates Abigail's history, her ruthless, plastic surgeon mother, Dr. Fine, decides to silence the curious but klutzy Lois by enforcing the surgery on Lois. Meanwhile, Martha accepts a job managing The Talon while Lois starts working for the school paper the Torch, and gets just a little closer to Clark.

The Smallville High cheerleaders are using a kryptonite mixed love potion to seriously change the behavior of their victims.

Clark meets a young man with a power of speed that exceeds his own, but the boy lacks responsibility for his actions. Also, Lex finds a manuscript that appears to be some sort of Kryptonian map.

Lionel Luthor, using one of the Kryptonian stones, attempts to swap bodies with Lex but inadvertently transfers bodies with Clark, leading to him learning a few secrets, including that of Clark's powers.

A mysterious bookie with powers of manipulation has a strange, even dangerous, effect on Clark and his friends. Meanwhile, Lex causes friction by using his influence on Jason and Lana's relationship.

In 1604, in southern France, Lana Lang's distant ancestor Countess Margaret Isabel Thoreau and two other evil witches are condemned to be burned at the stake by Magistrate Wilkins, but Isabel manages to spit her blood on a symbol on a page of their mighty book of spells. In the present day, Lana buys the book on eBay, and by touching the blood-spotted symbol, resurrects the evil countess who possesses her body. Isabel/Lana uses a spell to let the other two witches posses Chloe and Lois. The powerful trio vows to pursue its quest for the three (actually Kryptonian) magical stones which can bring them unseen power. The trio enters a 'surprise' birthday party for Chloe in the barn of the Kent Farm and Isabel throws a spell to make the spectacle really hot, so Clark is one of many boys dancing and drinking in boxer-shorts when his appointment arrives, a representative from Princeton University, who is impressed in a way which can't amuse Clark's parents. The vicious witches cast spells against Jason, who is thrown out of a window but caught just in time by Clark, and Lex, who is made to play the piano constantly so his fingers start bleeding till Clark shoves the piano away, and even to draw the super-power from Clark.

Lex gets wrapped up in a sex/murder scandal. Clark gets Lionel's help to get Lex out of trouble. Lana meets Jason's mother, whom she has seen before in a dream, which was set in the 1600s.

After an explosion at a LuthorCorp lab, Smallville's citizens "relive" their worst nightmares.

Alicia Baker returns, and with the help of Red Kryptonite, elopes in Las Vegas with Clark. Lana offers a sexual relationship to Jason in an attempt to win him back. Lionel comes back to Lex with a peace offering.

When Lana is attacked in her apartment and Jason in his car by an invisible being, everyone believes that Alicia Baker was responsible, except Clark. However after a series of circumstances, Clark begins to doubt Alicia's innocence to the mysterious attacks. Alicia tells Clark that she'll offer to prove her innocence if Clark reveals his own superpowers, but Clark refuses. So, Alicia secretly shows Chloe the abilities of Clark, expecting people to leave them both alone. But elsewhere, Lois discovers that the real culprit of the attacks is the deranged Tim Westcott who's jealous of Alicia's abilities which leads to him murdering her, and then goes after Clark. Meanwhile, Genevieve Teague arrives back in Smallville and approaches Lex Luthor to get his help to separate her son Jason from Lana.

Clark is wooed by the offer of a Football scholarship from Metropolis University but faces a dilemma over whether he should accept, knowing he has such an advantage on the field because of his superpowers. Meanwhile, Lois is implicated in the death of a member of the Metropolis University Football team which leads Clark to investigate to clear Lois in which they suspect that the team's idol, named Geoff Johns, may hold a clue. Elsewhere, Lex tries to persuade Lana that Jason's mother had ordered him to try to break her and Jason up for mysterious reasons.

As if Lois Lane didn't make enough of a nuisance of herself now living at the Kent farm, she brings in Einstein, a golden retriever, who is the latest victim to be hit by her car, and she meanly calls him 'Clarky', while Clark, kind as ever, hopes to keep him as a pet if the owner isn't found, which his parents hope. Clark soon finds out it's a surviving dog of an experiment to give canines superpowers with daily injections of steroids mixed with meteorite fragments (kryptonite) produced at LuthorCorp, which Lex insists to Clark that the project was abandoned after animal activist protests, thinking they were all put down. Only later Clark finds out, the hard way, the dog and a Rothweiler are abused by evil Josh Greenfield and his kid brother Zack, who run the Smalville animal shelter and abuse dog whistles to control the super-dogs as weapons for robberies. Meanwhile, Jason and his secretive and manipulative mother, Genevieve, are revealed to know more about Lex and his apparently reformed father Lionel, while Lana and Chloe all take a keen interest in the relevance of the Teague and Lang family trees, which have common roots in countess-witch Isobel's French place of origin.

The Kryoptonian metallic disc is returned to Clark following the death of Virgil Swann. Placing the disc in the cave reveals a message from the spirit of Jor-El instructing Clark to find the three Kryptonian knowledge crystals and unite them before others find them and use them to self-interest. The message goes on to tell Clark that allowing a human to assemble the crystals could lead to the destruction of Earth. The first stone, retrieved by Lex in Egypt in the season opener, is in Clark's possession in the cave. The second is apparently in possession of the late Swann's associates. And the third is located somewhere in China. Clark joins forces with Lana where they venture to China to search for the stone where Lex and Jason are also on the hunt for the stone. But they end up captured by the Chinese authorities and tortured for information to the stone's location, and it leads to the spirit of Isobel once again commandeering Lana's body to fight everyone to take the stone for herself.

When Jason arrives at Lana's apartment at The Talon, they see that is was broken into and wrecked. They discover that the magical stone they took from the Chinese temple is gone. Lana implores Jason to leave it, and concentrate on their romantic relationship instead. But the two meet at Lionel's office, who strongly denies any knowledge of the theft and accuses his son Lex, who makes another innocence-claimant. Meanwhile, the Kent farm gets an uninvited guest's guest: Lois Lane's younger sister Lucy, a violinist who left her fancy Swiss boarding school. The Lane girls start hanging out at Clark's place and at The Talon, where Clark catches Lucy stealing from the till; she says to be in debt with Swiss loan shark Marcus Becker "to afford the lifestyle" of the spoiled brats in her class. Lex knows Becker as member of a major crime syndicate he has business problems with, and offers to help. Becker isn't content to take Lex' money, he kidnaps the sisters to extort more, Clark decides it's time to use his superpowers.

An experiment with heated (black) kryptonite at Luthorcorp causes an explosion which badly wounds Dr. Sinclair, the scientist in charge, and creates a molecular copy of Lex which has the evil side of his personality. While the real Lex shows Clark the experiment was to create far stronger crops, the evil one gives Sinclair a fatal injection in hospital after questioning him. Fearing an effect on himself, 'Evil Lex' locks the good Lex up wearing an iron mask and sets out ruining lives in Smallville, such as closing The Talon when Lana refuses to be his girlfriend, and taunting Lionel Luthor badly enough to make him turn away from charity. When Chloe shows Clark proof on hospital video recordings there must by two Lex's, Super-boy is duped into telling the fiend everything, believing him to be the real one, so the Clark family and Chloe become his prime targets, and he knows about green kryptonite and its affect on Clark.

It's almost graduation, and that means it's time for the prom. After a car accident, a meteor-infected student in-the-run for Prom Queen starts body-swapping. Meanwhile, a dead body is found on Lex's mansion grounds.

Kevin Grady commits thefts and uses his superpower to delete the incident from witnesses' minds. When he does so with Clark who stopped him after robbing The Talon, much more memory gets wiped, so Chloe must take super-boy home to the Kent farm and help him remember who he is, including discovering together the amazing extent of his superpowers and his feelings for Lana Lang. Meanwhile Lana tells Jason she's neither sure she still wants to go to college nor to stay his girlfriend, claiming it's not Clark but their complicated past, he walks off angry, warning she doesn't realize how much he has been protecting her. Clark and Chloe trace a motor-park pass Kevin dropped to his home, or rather to his father Lawrence Grady, and gradually discover Kevin is in memory manipulation therapy with him in Summerholt neurological institute, where Lex once was a patient, for a hunting accident killing his brother Dillon but escaped. Clark helps Kevin...

In the middle of the night on the road, a young pregnant woman is going into labor while the father of her child drives, when she suddenly glows and implodes, while the guy stops the car and runs for his life. Lana and Clark are driving a truck along the same road and find a baby in the crater created by the explosion. They take the baby to the hospital, and the Kent family temporarily guards him, who is connected to Clark. Lana and Clark give the name of Evan, and on the next day, he becomes a teenager, precociously aging. The scientists of Lex study the case and conclude that the boy needs a transfusion of the bone marrow of his unknown father, if he can be found, and even then... Clark tries to save Evan. Meanwhile, Genevieve Teague has a meeting with Lionel Luthor and threatens to hurt Lex, in case the missing stone from China is not delivered to her. But Lionel soon turns the tables on Genevieve by poisoning her (the same way he unsuccessfully tried to poison Lex in the previous season) and threatens not to give her the antidote unless she gives him the second missing stone whom she in fact stole from the murdered Bridget Crosby.

On the last day of Smallville High before graduation, the emotionally disturbed and frustrated photographer of the Torch, Brendan Nash, feels rejected by the Universities and decides to abduct some schoolmates to stay with him forever in a replica of the school. He uses his power of 'Medusa Touch' of turning people into stone by mere touch, and brings Lana, Chloe, and other successful schoolmates to the place. While Clark teams up with the nosy Lois to find the other students, he also talks with Jonathan and Martha over his college choices after graduation. Meanwhile, Genevieve and Jason Teague kidnap Lionel and Lex Luthor and hold them hostage in a remote mountain cabin and torture both of them to try to retrieve the second mystical stone that Lionel took from them.

When Lana (possessed by Isobel) kills Genevieve Teague by stabbing her with one of the Kryptonian Knowledge Crystals after she attempts to steal it, it triggers a cosmic event that not only severs Lana's link to the spirit Isobel but also sends meteorites from deep space toward Earth and Smallville. At the graduation ceremony for Smallville High, the military arrives to evacuate the town after news that another meteor shower is imminent. Fearing he has a link to the meteorites, Clark goes to talk to the spirit of Jor-El, who informs him that his only hope is to unite the knowledge crystals in the cave. With time running out, Clark sets about locating the final two crystals as meteorites reign down upon Smallville. Lana gives Clark the third stone they recovered from China, which was in her possession all this time, while the second stone is on Lionel's person, which activates. Lex offers to protect Lana and have her flown to New York City, but she gets caught in the meteor shower while riding in a helicopter. Lois manages to get out of Smallville in time, but Chloe stays behind to follow Clark who retrieves the final one from Lionel which hits them with a burst of energy driving him comatose. Chloe helps Clark retrieve the final stone from the Luthor mansion safe after he is immobilized by kryptonite, and helps him escape from Lex. Clark manages to unite all three stones, which transports him to the wild tundra of the frigid North Pole...