Lincoln Burrows is currently on death row and scheduled to die in a few months for an assassination his younger brother Michael is convinced he did not commit. With no other options and time winding down, Michael takes drastic measures to get himself incarcerated alongside his brother in Fox River State Penitentiary. Once he's inside, Michael, a structural engineer with the blueprints for the prison, begins to execute an elaborate plan to break Lincoln out and prove him innocent.

In season two, Michael, Lincoln and six other inmates, including pickpocket Tweener and the mentally unstable Haywire, have ultimately escaped from Fox River. Once outside the prison walls, however, the escape truly begins as the convicts race for their lives while trying to avoid capture by the authorities. The pursuers are led by FBI agent Alexander Mahone, who is haunted by his own demons; vengeful prison guard Captain Brad Bellick, who, driven by his own personal vendetta, will also stop at nothing until the escapees are captured or killed; and Secret Service Agent Paul Kellerman, who, under President Reynolds' orders, will do anything to keep the truth about the conspiracy very much a secret.

Just when they thought they were out, they are pulled back in — for the most dangerous escape ever. Season three finds Michael Scofield wrongly incarcerated in Sona, a hellish Panamanian prison where there are no rules, no guards, and no escape.

After engineering a daring escape from the hellish, Panamanian prison Sona, brothers Michael Scofield and Lincoln Burrows are determined to seek justice against The Company, the shadowy group responsible for destroying their lives and killing the woman Michael loves, Dr. Sara Tancredi. Michael’s quest for vengeance leads him to Los Angeles, where his world is turned upside down when Company operative Gretchen/Susan B. Anthony informs him that Sara is still alive. Realizing the only way they will truly be free, Michael and Lincoln avow to find Sara and take down The Company. With the help of Homeland Security agent Don Self, they assemble a group of allies and familiar faces to accomplish their task: Mahone, Sucre, Bellick and computer expert Roland Glenn. Unfortunately for the brothers, they must also evade company assassin Wyatt and find an on-the-loose T-Bag. Michael and Lincoln soon discover the only thing harder than breaking out will be breaking in.

Seven years later, thanks to an information provided by T-Bag, Lincoln and Sara discover that Michael is still alive in a Yemen prison, so they develop a plan to get him out.