Picking up eight hours after their escape from Fox River, Michael, Lincoln, Sucre, Abruzzi and C-Note are on the run for their lives as a vengeful Bellick leads the prison guards seeking to capture their escaped quarry; Dr.
Abruzzi, Sucre and C-Note make a run for it on their own; Michael and Lincoln plan another breakout this time to rescue a jailed LJ, whom Mahone targets in his quest to capture the escaped cons; Bellick and Warden Pope face a jury of their peers regarding the prison escape; Tweener hitches a ride with the college crowd; and T-Bag takes drastic measures to get the upper hand.
Michael and Lincoln experience car trouble as Mahone's pursuit of them goes up in flames; Sucre hits the road to stop Maricruz from taking a gamble; C-Note is determined to reunite with his wife and daughter despite their surveillance; a familiar face keeps a close eye on Sara, who finds the tables turned on her; determined to cash in on the prison break, Bellick partners with an unlikely ally.
Bellick, now teamed up with Michael, Lincoln and Nika, sets out to find the money stolen by Westmoreland during the 1971 skyjacking. Kellerman targets Sarah, who receives a long-awaited phone call. T-Bag gets a ride from an unsuspecting family. Abruzzi resumes the search for Fibonacci to settle the scores once and for all.
Mahone takes a sudden interest in the "myth" of DB Cooper and receives a special delivery at FBI headquarters; Michael and Lincoln are determined to be the first to find the location of Westmoreland's Double K ranch in Utah; T-Bag hopes his memory doesn't fail him; C-Note has a bumpy train ride; Sucre races to Las Vegas to stop Maricruz's wedding; Kellerman gets his foot in Sarah's door.
In their quest to find Westmoreland's treasure, Michael and Lincoln travel house-to-house in Utah. Haywire's journey outside the prison walls continues. Sucre bumps into an acquaintance.
Lincoln wants to reunite with LJ, who is suspicious of his good fortune in Arizona; Michael, C-Note, Sucre and T-Bag's hunt for buried treasure pays off; Kellerman has a change of heart just as Sarah is targeted by The Company; and Mahone forces Tweener to make a deadly choice.
Michael has his hands full when Sucre turns traitor and escapes with the newly found $5 million; Mahone is investigated by Internal Affairs regarding Tweener's death; Lincoln is determined to reunite with LJ, but may be walking into The Company's trap; and Sarah must fight for her life when the conspiracy tries to make history repeat itself.
Michael puts the moves on Mahones wife in hopes of digging up dirt on his pursuer. Lincoln and LJ have an uneasy road trip; C-Notes wife must choose between her husband and daughter; and T-Bag gets an unwelcome surprise while looking for a lost love.
Michael and Sarah's reunion is anything but romantic as Mahone and Kellerman are determined to keep them apart permanently; Lincoln receives some help from a father figure as LJ meets a long-lost relative; Sucre plans a getaway with Maricruz; and T-Bag runs into a familiar face while holding the key to his freedom.
Lincoln must say goodbye to yet another loved one as he attempts to reunite with Michael; Michael's attempt to secure a getaway plane is grounded; Mahone deciphers a crucial puzzle piece; T-Bag gets his revenge on his tormentors; and Sarah and Kellerman have a tense face-off that leaves one of them gasping for their last breath.
A family reunion brings up painful memories of Michael's childhood. Mahone tracks an injured Coyote to lead him to the getaway plane. C-Note gets a taste of some bad medicine. Meanwhile, agents Bellick and Kellerman get the third degree from the women in their lives.
T-Bag goes postal to track down a missing Mrs. Hollander. Sucre's escape plane faces deadly turbulence. Bellick has the tables turned on him upon his return to Fox River Penitentiary.
Michael, Lincoln and Kellerman face several roadblocks as they attempt to capture a protected Terrence Steadman; tragedy strikes the Mahone family; Bellick turns sour when a fellow inmate turns sweet on him; C-Note faces life on the run as a single parent; and T-Bag forces the Hollander family to play house with him.
Michael, Lincoln and Kellerman take the airwaves hostage as they attempt to evade the authorities and get a message to a missing Sara; Bellick gets a surprise visit in Fox Rivers infirmary; Haywire resurfaces and lands in more trouble; Sucre takes his good Samaritan for a ride.
Michael and Sarah become more than strangers on a train en route to confront the President; Mahone recruits an new ally in his attempts to capture the fugitives; T-Bag puts on a happy face when the welcome wagon arrives; and a fourth escapee takes a fall.
Michael and Sara request Henry Pope's help to retrieve the information that will topple The Company. Mahone pins down an escapee. Sucre discovers a new threat while hitchhiking to reunite with Maricruz. T-Bag brings the Hollander family to his home.
T-Bag digs deep and finds his 'nice-side' with the help of a psychiatrist. Michael, Lincoln, and Sarah get their hands on evidence needed to bring down The Company, while Kellerman is close to finding the President.
As Kellerman prepares for an assassination, Michael is determined to confront the President and expose her secrets recorded on the audiotape. Mahoney plays a tense waiting game with Sarah. T-Bag's lost luggage may prove a windfall for Bullock and Sucre. C-Note's drastic actions leave him hanging.
Sarah considers sacrificing her freedom, in an effort to allow Michael and Lincoln the opportunity to escape. T-Bag continues to terrorize south of the border, as Bellick forces Sucre to find the missing money. Mahone’s actions finally catch up with him, and an escapee tastes freedom.
Michael is determined to get his hands on T-Bag as much as Bellick is determined to get his hands on the millions, Lincoln and Mahone square off, while Sarah faces judgment day and Kellerman decides his own fate.
Michael tries to save his brother and himself from the unstoppable Mahone. Kellerman's testimony at Sarah's trial proves different from what was expected, could this be the end for Sarah? Sucre puts everything on the line to save his Maricruz. Just like old times, T-Bag and Bellick are at it again but this time there will be a winner.