The escape is about to go through when the team hits a stainless steel snag, while Veronica is just a moment too late to get all the information she needs to prove Lincoln's innocence.

Flashbacks provide exposition on how the inmates arrived at Fox River Penitentiary from The Company's framing of Lincoln to the creation of Michael's plan to save his brother's life.

With hospitals and clinics under surveillance, Michael brings Lincoln to Nika's home to heal his wounded leg. Then he returns to the place where he parked his Accord and finds that the car has been towed. Meanwhile agent Mahone retrieves Michael's backpack with his passport from a vagrant that broke the rear window of Michael's car to steal the backpack. Michael goes to Brewster Towing yard to recover his car. Meanwhile Sucre finds that Maricruz will marry Hector in a couple of days and he heads to New York in a stolen car. Sara is arrested and her father visits her, pays her bail and orders her to tell a fake version about the incident in Fox River since he will be the next Vice-President of United States. Later she goes to rehabilitation where Kellerman is pretending to be an addicted patient. C-Note schedules a meeting with his wife, but his conversation is bugged by agent Mahone. Bellick and Geary meet each other by chance and later they team-up to get the $400,000 reward for capturing Michael and Lincoln. They go to Fox River and Bellick interrogates Manche Sanchez, who discloses the plan of the fugitives. Michael and Lincoln forge a car accident to escape from Mahone, but they do not see that Bellick and Geary are in their tail.

Michael tries to retrieve an item from Blanding Botanical Garden in Utah, but Mahone's people got to it first. Mahone believes that someone on his team is leaking information to the press; meanwhile Michael does some research on Mahone at an Internet café, then makes a trip to Durango, Colorado, to see a woman there. Linc and L.J. are on the road in Arizona. C-Note is in Chicago, and Agent Lang tries to use his wife to capture him. Bellick and Geary phone C.O. Patterson, at Fox River, to get information on where they should look for T-Bag. Sara is at a motel in Elgin, Illinois, trying to crack Michael's code. T-Bag arrives in Tribune, Kansas, for (as he puts it) "romance". Kellerman is on the trail of Sara.

Picking up from where we left off, Sucre, Michael, Linc, and Aldo are together, with Mahone on their trail. Sara is face-down in the bathtub as Kellerman prepares to dispose of her body. C-Note is in Harvey, North Dakota with Kacee and Dede, who needs her medication. In Tribune, Kansas, Detective Slattery questions Bellick.

Linc and Michael have decided to take the keys and escape, figuring at least they'll go down fighting. FBI Special Agent Alexander Mahone chased them while staying in contact with Secret Service Special Agent Paul Kellerman who suddenly shot Mahone and gave the brothers a ride because he wants revenge on the White House; Linc wants his instead, but is offered the location of Terence Steadman. T-bag visits his ex-girlfriend, who tells him the children think he's their Uncle Teddy on an oil rig, but he moves in; when she goes for a gun, he attacks her and her son attacks Zach him, so he turns the home into a private prison. In prison, former boss Bellick, who naively had made a deal in order to do his time in Illinois, shivers in general population among the prisoners he abused and their mates, he has none as the new warden sees him as an example of his new, clean ship; he soon realizes there's no pleasing them, and tries hitting hard; a loyal guard warns him the night shift is on his enemies side as he treated them badly. Benjamin Miles 'C-Note' Franklin tries to save his Kacee who is in custody, advising her to put all the blame on him; after hearing how scared his girl is, he asks one of his friends for help to run while she's on bail but the judge refuses bail. Mahone awakes in hospital, and reports to Kim on Kellerman's betrayal and the brothers' escape, which is hitting the TV news, but refuses to play anymore, even if that means jail; when his wife Pam phones their son is hurt he rushes out for Colorado, but is stopped to hear it's a warning to force him back in line; however he is through doing Kim's bidding and shoots his man. Kim calls Steadman's bodyguards: he must be evacuated to a safe house as Kellerman knows his residence, but he is already there with the brothers- Kims orders to kill everyone, but only the FBI men are shot; Kellerman explains Steadman is made unrecognizable, including plastic surgery, so their only option is to get him to Washington, where FBI agents who know can still make the truth stick. Michael decides instead to turn himself in while informing the press, despite Kellermans gun aimed at him, but Steadman prefers to commit suicide, and his corpse is worthless for the brothers.

Sara meets Michael and Lincoln in a train station in Evansville, Indiana; when she sees Kellerman with them, she becomes disturbed and upset. Kellerman tells that she has a key of a private cigar club in Chicago. Caroline calls Kellerman and he tells that he is heading to Chicago by train, and she promises his life back, inclusive the chief of staff position. T-Bag tells Susan that they are passing through an "adjustment period" in their lives; when she tells him that she will have a guest called Patty Wallace, T-Bag welcomes Patty with a magnificent family brunch and uses the strong father figure to discipline Zack, seducing the guest with his charm and attitude. Wheeler is reporting the actions of Mahone to the FBI Headquarter and they find that Haywire killed a man in Algoma, Wisconsin. Mahone visits Bellick in River Fox, releases him using a habeas-corpus to make his dirty work, and gives a car, a pistol and an FBI badge to the despicable man. Bellick chases and traps Haywire, and waits for Mahone. In Benson, Minnesota, C-Note and Dede are leaving a snack bar when an addicted thief announces a heist. When Kellerman sees a road block on the train, he realizes that he was betrayed.

Michael Scofield and Sara Tancredi fail to get the tape from the Corona de Oro cigar club in Chicago, where security was at the ready, and turn to former warden Henry Pope, a club member, but he wants to call the police. Michael draws his gun and hands it over to prove his veracity; Sarah convinces him to go in with her late father's humidor key and he finds a computer memory stick. In Mexico, Fernando Sucre has car trouble and gets a ride from an Ixtapa airport security employee who sees his wanted-poster just after they parted at the airport, so he must run with his bride. T-bag and his forced-along family find his own house vandalized and looted except for the family bible, which arouses in him youth memories of his perverted father, and assures Suzy he wants their love and is happy to be infertile, her bloodline should take the Bagwells's place. When she refuses, he locks them up, considers ax-murdering but just leaves them behind. FBI Special Agent Alexander Mahone has tracked down Benjamin Miles 'C-Note' Franklin and his daughter, but lets them escape in a bus rather than shoot the kid. C-Note brings her to a doctor, worried about the kidney disease PKD, but won't allow inserting a catheter, rather turns himself in to Mahone, who is with his own boy in Colorado, and makes a deal to get him Scofield. Pope is out of the club, but is greeted at the entrance by Secret Service Special Agent William 'Bill' Kim whom only Paul Kellerman, watching from a roof with Linc, knows by sight. Michael drives over Kim and gets away with Pope, Sarah and Linc, locking Kellerman out. When Michael tells the others he's prepared to honor his promise to Pope (which the others didn't know about) to turn himself in for his help, Henry hands him the stick and lets them go.

Now that Caroline Reynolds has stepped down as president, she can no longer sign a pardon, so the brothers must immediately disappear, forever. At the pier Sarah realizes she's being tailed and pretends on the phone already to be on board, so they sail without her while she is arrested. Lincoln stops Michael from returning for her. A week later, an FBI bigwig offers C-note a lesser sentence for testimony against Mahone, even freedom and witness protection for his family- bingo. Fernando grabs Bellick's gun while looking for T-bag, but Bellick shows a crucifix to prove he has Maricruz. The scumbag enjoys his fortune with a lady of the street playing his Susan-Q. The brothers arrive at Cristobal, Panama. Meanwhile Malone's team deduces Scofield's tattoos refer to Michael's mother Christina, presumably dead, and he presumes his computer contained much info on Panama for a reason. The man in power grills Kim on a small boat, and decides to change the strategy. Mahone sees through FBI-colleague Wheeler. C-note is reunited with his family and released. The brothers have a fight, torn by guilt for too many innocent people suffering through their well-meaning deeds, then board a yacht, named- Christina. Mahone tells Kim he's not happy with the results as he remains separated from his family, but is told he now needs help to escape, and therefore must go to Mexico- to help T-bag.