Michael Scofield escapes from Sona, a deadly Panamanian prison to find Whistler, a mysterious fellow inmate hiding within the prison's sewer system, in order to break him out from a prison which has no way out. Meanwhile, Lincoln searches for missing Sara and receives troubling news about LJ.
Michael races to find a hidden Whistler before Mahone. Lincoln runs into an old friend and makes a new one while searching for clues outside the prison. T-Bag slithers his way into Lechero's graces as the prisoners threaten a revolt due to the lack of water.
Michael is determined to speak with Sara. He enlists T-Bag's help to get to the only phone in Sona: Lechero's. Lincoln attempts a daring rescue. Whistler comes clean to Michael, just as Mahone is tempted to fall back on a dirty habit; and Bellick makes an enemy while attempting to get back on his feet.
Having failed in his attempt to rescue LJ and Sara, Lincoln receives a deadly warning from The Company. Michael formulates an electrifying escape plan from Sona. Mahone is haunted by a face from the past. T-Bag crawls up the ladder as Bellick lands in hot water with Lechero.
A new inmate enters Sona, unnerving Whistler and raising Michael's suspicions; Lincoln plans an ocean getaway with Sofia as Susan moves up the escape timetable; T-Bag tempts his fate with his latest attraction; and Sucre attempts to get the goods into Sona.
When an inmate is found murdered, Whistler becomes the prime suspect and Michael must prove his innocence in order to save his life. Michael demands evidence from Susan that Sarah is alive, or he will cancel the escape.
Lincoln and Sofia monitor the guards' morning rituals, meanwhile Mahone gets an offer that may get him a ticket out of Sona.
Susan takes the escape into her own hands, leaving Michael's life hanging in the balance. Lechero reveals a secret buried beneath Sona; Sofia uncovers more of Whistler's past. Mahone's freedom hinges on his testimony; and Lincoln and Sucre are targeted by The Company.
After raising the suspicions of the Panamanian Army, Michael experiences solitary Sona style. Bellick has the fight of his life and Susan sets her sights on Sucre as T-Bag schemes his way into the escape.
When Luchero loses his authority over Sona, Sammy causes Michael's escape plan to come crashing down. T-Bag pressures Bellick to one more fight that will likely be his last. Lincoln and Sucre plan an explosive end for Susan.
Heavy rains force Michael to move up the escape timetable and break out of Sona that evening. Another inmate joins in the escape, and T-Bag and Lechero form an alliance as Bellick hopes to form one with Mahone. Lincoln and Sucre help bring the lights down on Sona.
Michael and his fellow inmates make their break from Sona, but the escape doesn't go as planned for all of them.
In the season finale, Michael and Lincoln must hand over Whistler to Susan so they can save LJ and Sofia's lives. Meanwhile, Mahone seizes a golden opportunity, T-Bag shows Sona who's boss and a familiar face enters Sona as another leaves it in a body bag.