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. Sara is in critical condition from her overdose; Veronica finds herself a prisoner with Terrance; T-Bag tries to get the upper hand while fleeing from the authorities; and a new take-charge FBI investigator proves to be Scofield’s match.

Now outside the prison walls, Michael, Lincoln and six other escapees race for their freedom as the authorities close in on them. Caroline Reynolds is abandoned by the Company and decides to take matters into her own hands. Veronica arrives in Montana to find the evidence that will prove Lincoln’s innocence.

Michael betrays Pope in order to have Lincoln released from the solitary. Sara is faced with the decision to aid Michael’s escape or not. Nick is forced to betray Veronica. The escape team attempts a prison break.

After Bellick discovers the hole, the team resolves to make their escape immediately. With no time and no alternatives, Michael is forced to involve Sara in the breakout. Tweener joins the team. Veronica finds evidence leading to Blackfoot, Montana.

Michael must get the key to the infirmary and enlist the help of an old face, while Lincoln learns the identity of his kidnapper and another inmate learns of the escape.

In an effort to recreate the missing piece of the tattoo, Michael gets transferred to the psych ward, seeking the help of Haywire. T-Bag and C-Note have to join forces.

Lincoln is worried about Michael’s sanity while Michael has trouble remembering some parts of the prison schematics. Sucre has to conceal the hole in the guard’s break room. Warden Pope transfers Michael to solitary after he declines his request.

Flashbacks shed light on the past actions that led to the incarceration of Lincoln, Sucre, T-Bag and C-Note. The basis of Michael’s ingenious break-out plan is revealed. Dr. Tancredi recalls how she ended up in Fox River State Penitentiary.

As Lincoln is about to be executed, he sees his father in the viewing room. A phone call from Judge Kessler delays the execution. After reviewing the newly surfaced evidence, the judge orders the exhumation of Steadman’s body. Michael creates a new, more dangerous, break-out plan, involving going through the prison yard. An accident puts Michael’s new plan in danger.

Michael and the other prisoners attempt to return to their cells without being detected. Veronica and Nick take Lincoln’s case before a judge. Sara asks her dad, the governor, to review Lincoln’s case. Michael tries to postpone the execution by fiddling with the chair’s wirings.