The first season follows the rescue of Lincoln Burrows (Dominic Purcell), who is accused of murdering Terrence Steadman (Jeff Perry), the brother of the Vice President of the United States. Lincoln is sentenced to death and is incarcerated in Fox River State Penitentiary where he awaits his execution. Lincoln's brother, brilliant structural engineer Michael Scofield (Wentworth Miller) , is convinced of Lincoln's innocence and formulates an escape plan. In order to gain access to Fox River, Michael commits an armed robbery which results in his being sentenced to Fox River. In prison, Michael befriends the prison doctor Sara Tancredi (Sarah Wayne Callies) when he pretends to suffer from Type 1 diabetes, in order to gain daily access to the prison's infirmary. The brothers' fight to ward off the execution is aided by their lifelong friend Veronica Donovan (Robin Tunney), who begins to investigate the conspiracy that put Lincoln in jail. However, they are hindered by covert agents, members of an organization known as The Company. The Company was responsible for framing Lincoln, and they did so because of Lincoln's father, Aldo Burrows, and his former connections to the company. The brothers, along with six other inmates, Fernando Sucre (Amaury Nolasco), Theodore "T-Bag" Bagwell (Robert Knepper), Benjamin Miles "C-Note" Franklin (Rockmond Dunbar), David "Tweener" Apolskis (Lane Garrison), John Abruzzi (Peter Stormare), and Charles "Haywire" Patoshik (Silas Weir Mitchell), who come to be known as the Fox River Eight, escape in the season finale.
The second season begins eight hours after the escape, focusing mainly on the escapees. The fugitives split up and journey to locations across the country with the authorities close behind them as they each pursue their individual goals. Brad Bellick (Wade Williams) gets fired from the prison where he worked as a guard and chases after the inmates himself for the reward money. Several of the escapees reunite in search of a large cache of money buried long ago by another prisoner. Federal agent Alexander Mahone (William Fichtner) is assigned to track down and capture the eight fugitives, but is revealed to be working for The Company, which wants all eight men dead. When Sara discovers her dead father, Governor Frank Tancredi, she meets with Michael, remaining with him as the brothers try to bring down the current President, a Company member. To ensure the brothers' safety, Sara allows herself to be arrested and faces trial. During the trial, the testimony of former Secret Service agent Paul Kellerman, who used to work for the Company-controlled President, exonerates Lincoln and Sara. Several of the escapees are killed or recaptured, but the brothers make it to Panama. Michael, T-Bag, Mahone, and Bellick are arrested by the Panamanian authorities and imprisoned at the Penitenciaría Federal de Sona.
The third season follows both Michael inside Sona and Lincoln on the outside in Panama. Sona is a prison that has been run by the inmates and guarded only from the outside since a riot the year before. Burrows is quickly contacted by Gretchen Morgan (a Company operative who was in charge of operations in Panama) who kidnapped his son LJ (Marshall Allman) and Sara Tancredi (Sarah Wayne Callies), the woman Michael loves. He is told that The Company wants Scofield to break James Whistler (Chris Vance) out of Sona. The season follows Michael and Whistler's trials in formulating an escape plan, as Michael has to deal with extreme tension and as Lincoln deals with the Company's operative Gretchen Morgan (Jodi Lyn O'Keefe). Sucre gets a job at the prison to aid Michael in his escape plan. When Lincoln attempts to rescue Sara and LJ following a clue provided by Sara, Gretchen claims to have beheaded Sara and sends Lincoln a head in a box as a warning. As the season ends, the pair manage to escape along with Mahone, and another inmate McGrady leaving behind several accomplices including T-Bag and Bellick. Sucre's identity is discovered by a prison guard and he is thrown into Sona just after the escape. LJ and Sofia (who was captured for a guarantee that Whistler would go with her) are traded for Whistler, and Michael seeks revenge against Gretchen for Sara's death.
The major storyline for the fourth season concerns a team recruited by Homeland Security agent Don Self (Michael Rapaport) to obtain Scylla. Although the team initially believes it to be the Company's "black book", it is later revealed to contain information on an advanced renewable power cell. Over the course of the first half of the season, the team obtain cards to access Scylla, and break into Company headquarters to steal it. In the first half, Sara is discovered to be alive, Bellick is killed, and Self is revealed to be a double agent and is planning to sell Scylla to the highest bidder. Reluctantly, Lincoln decides to join the Company to get it back, while Michael suffers from a hypothalamic hamartoma. He is treated and operated on by the Company. He later learns that his mother, Christina is still alive and was an agent of the Company, who is revealed to acquire Scylla to sell to the highest bidder. Eventually, the series ends in Miami, where Scylla is recovered by Michael and the team, the General and the Company are taken down, and Christina is killed. In Prison Break: The Final Break, a story is told explaining what happened following the events of the last episode (before the four-year flash-forward) and the strange scar on Sara's shoulder. This story involves the incarceration of Sara in Miami-Dade county penitentiary due to budgetary cutbacks; there are cots installed there acting as the county jail. With the General and T-Bag in the adjacent Men's facility, the General wants Sara dead and offers a $100,000 bounty. Largely echoing season one, Sara is involved in common prison fare before Michael hears of the bounty, and plans are devised for her escape. And in the end, Michael sacrifices himself for his brother, wife and child. It was also his choice to do, due to his disease, a brain tumor. (Piyush)