As Season 3 begins, Michael, Mahone, T-Bag and Bellick are all in Sona, a notorious Panamanian prison. “The worst of the worst are there,” a U.S. diplomat tells Linc. The good news is that Linc has been exonerated, and Michael is to be transferred to a “more moderate” prison before his trial. But first Michael must deal with the prison's ringleader (Robert Wisdom). And the Company's interested in him, too. Meanwhile, Sara's missing.
After Michael gets bad news from Linc, he sets out to find a prisoner named Whistler (Chris Vance), who holds the key to his freedom. That's easier said than done: Whistler is hiding in Sona because there's a price on his head, and Lechero (Robert Wisdom) is not about to help Michael find him. In addition, both Mahone and Bellick want to get to Whistler too. Meanwhile, T-Bag won't allow a little humiliation stop him from insinuating himself into Lechero's good graces.
Someone slides an envelope containing a photo of Sara and LJ under the door of Linc's hotel room. It might contain clues to their whereabouts. The Company Operative (Jodi Lyn O'Keefe) in Panama City might help, too, but Linc must persuade her it's in her best interest to do so. And at Sona, Michael gets to know Whistler (Chris Vance); Lechero begins to lose confidence in his ability to shape events; and Mahone, who is in increasing need of his medications, meets the lawyer who'll defend him.
After failing to rescue LJ and Sara, Linc receives an ominous warning from the Company; Michael plans an electrifying escape from Sona; a face from the past haunts Mahone; T-Bag crawls up the ladder while Bellick lands in hot water with Lechero.
A new inmate enters Sona, unnerving Whistler and raising Michael's suspicions; Linc plans an ocean getaway with Sofia as Susan moves up the escape timetable; T-Bag makes a friend; and Sucre makes a deal with a devil.
When an inmate is found murdered, Whistler becomes the prime suspect and Michael must prove his innocence in order to save his life. Michael also demands evidence from Susan that Sara is alive, or he won't help Whistler escape. Meanwhile, Linc and Sofia monitor the guards' morning rituals; and Mahone receives an offer that could get him out of Sona.
The Company has given Linc four days to get Whistler out of Sona, but Susan B. decides to act on her own, bypassing Michael, who finds a new ally in Sona. Meanwhile, Lechero faces a challenge from Sammy; Linc and Sucre try again to rescue LJ; Sofia learns some new things about Whistler; and Mahone, still strung out, testifies.
Michael finds himself in solitary confinement and must talk his way out. His interlocutor: Sona's new commanding officer. Meanwhile, Susan B. finds a way to keep Linc motivated; Lang has a parting gift for Mahone; Sucre makes another delivery to Sona and Susan B. makes him an offer; T-Bag makes Whistler an offer and Sofia confronts him; Bellick's refusal to mop up a mess puts him in a very messy situation; and a mysterious American woman travels to Panama to see Michael.
Michael heads back to shore up the escape tunnel, and T-Bag enlists Bellick to display his gladiatorial skills once again as the battle between Lechero and Sammy for control of Sona comes to a head. Meanwhile, in Panama City, Linc does a computer search on "Gary Miller," and Sucre has two meetings with Susan B.
Michael begins a new effort to tunnel out of Sona, joined by Lechero, Whistler, Mahone, Bellick and T-Bag. They are a team in name only. Then the weather causes a change in plans, requiring some last-minute assistance from Linc and Sucre. In Panama City, Susan B. threatens Sucre with the worst thing he can imagine. She also wants to see Sofia.
The escape attempt succeeds for some, if not all, of the escapees, and those who make it receive assistance on the outside from an unlikely source. But one escapee inadvertently leaves something behind.
Michael and Linc make their way to Panama City and their date with Susan B., but Whistler isn't with them. Meanwhile, Mahone waits for an appointment at a Panama City cantina; and McGrady and his father run into a roadblock on their way out of the country. Back at Sona, Sucre pays the price for the escape, while T-Bag comes to Lechero's aid and also takes stock of the new landscape behind the walls.