Michael Scofield gets imprisoned in Fox River State Penitentiary as part of an elaborate plan to break out his brother, Lincoln Burrows, who is facing execution for the murder of the Vice President's brother, a charge Burrows denies. At first Scofield gets the displeasure of C.O. head Brad Bellick and then meets his cellmate Fernando Sucre. Scofield forces John Abruzzi to recruit him in the Prison Industries (PI) by proving to know the location of Fibonacci, the only witness against Abruzzi. Scofield also meets Charles Westmoreland, who is believed to be D. B. Cooper, and Dr. Sara Tancredi, who injects him insulin because of his apparent diabetes, and Benjamin Miles 'C-Note' Franklin, who accepts to get anti-insulin drugs for Scofield. Scofield accepts warden Pope's offer to finish making a model of the Taj Mahal. Scofield reunites with Burrows, and reveals that his mysterious body tattoo is the blueprint of the prison. Meanwhile, L.J. Burrows, Lincoln's son, is arrested for drug dealing. Secret Service is revealed to be part the conspiracy against Lincoln. Veronica Donovan, a lawyer and Lincoln's former girlfriend, begins to believe his innocence.

Sucre goes to solitary confinement for keeping illegal materials. For his plan, Scofield needs an Allen bolt, which exists in Bagwell's bench. Bagwell refuses to give him the bolt after Scofield denies his sexual offer. Tancredi doubts Scofield's diabetes and schedules a test. A race fight starts between the black and white prisoners. Scofield obtains the bolt and uses it to unscrew his cell's toilet. Bagwell thinks that Scofield killed the former's male love. Franklin gives Scofield the drug, resulting in the latter's positive test and his regular access to the infirmary. Falzone, Abruzzi's accomplice, pushes him to find Fibonacci. Bellick searches Scofield's cell, but he doesn't find anything. Burrows tells Donovan that he didn't pull the trigger, as shown in the tape, and the man was already dead. Donavan finds a witness named Leticia Barris. Secret Service agent Paul Kellerman reports Donovan's activities to a woman in Montana. Since Sucre can't call his fiance, Delgado, from the solitary, she gets upset and goes out with a man named Hector. Scofield is abducted by Abruzzi's men and tortured for Fibonacci.

Lincoln vows to make Abruzzi pay, but Scofield reminds him that Abruzzi is needed. Sucre is released from solitary and Scofield tests the former's loyalty before revealing his plan. Sucre passes the test, but he decides to change his cell and stay out of trouble as he will be released soon. Abruzzi realizes that he must befriend Scofield in order to find Fibonacci. Bagwell plans to lynch Scofield. Abruzzi tries to reconcile with Scofield by having his men beat up Bagwell and thus the latter going to the solitary. Scofield tells Abruzzi about his plan and he agrees to cooperate. L.J.'s probation officer forces him to visit Lincoln and the father and son become closer after a long time. Before Barris can sign her testimony for Lincoln written by Donovan, Kellerman and his fellow agent, Hale, abduct and kill the former. Donovan decides to leave her fiance, Sebastian Balfour. Bellick brings Patoshik, a psychotic inmate, to Scofield's cell. Patoshik becomes a problem for Scofield's plan.

Patoshik is obsessed with Scofield's tattoo; knowing it to be a path. Abruzzi pushes Scofield to take care of Patoshik. When Sucre discovers that Hector is making a move on the former's fiancee, he decides to join Scofield's plan; but the latter tells him that he needs to get rid of Patoshik first. Scofield forms a hole to the infirmary using chemicals provided by Abruzzi and Patoshik's toothpaste. After a scenario made by Scofield, the guards take Patoshik away and Sucre is returned. Sucre starts a commotion in the block to cover for Scofield's noise. Scofield manages to open a hole behind his cell's toilet, opening a way to the corridors behind. In the meantime, with Lincoln's hint, Donovan asks Project Justice for help, which is denied; but Nick Savrinn from the Project decides to join her investigation. Kellerman and Hale learn that Scofield and Lincoln are brothers and arrange to transfer Scofield to a different prison the following day.

Pope denies Kellerman and Hale's request to have Michael transferred out of Fox River. They threaten Pope to reveal the latter's illegitimate son's history to his wife. Pope informs Scofield of the transfer. Westmoreland advises Scofield to write a petition to the court; which will delay the transfer for weeks no matter the petition's result. The agents tell Pope to throw the petition away. In the meantime, Scofield enlists the team's help to discover part of the escape route, whether to take one of the streets English, Fitz or Percy, outside the prison. He has the guards believe that he attempts to escape, where he discovers police cars flooding English and Percy, but not Fitz. In order to prevent any more troubles, Pope decides to have him transferred; but changes his mind at the last moment and proceeds to tell his wife the truth. Meanwhile, Donovan and Savrinn realize that the tape against Lincoln is faked, but it gets stolen, and she suspects he is working against her.