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.