Lincoln Burrows is on death row for the murder of the vice president's brother. He insists he's innocent and only his brother Michael Scofield believes him. As an engineer who helped design the prison where Lincoln is being held, Michael takes drastic measures to help his brother. He gets himself arrested and sent to the same prison so that with his knowledge of the building the two of them can escape together. However, while inside, Michael discovers a massive conspiracy that is determined to see Lincoln's sentence carried out. Breaking out will be more difficult than he thought, but he's still going to try.

Season 4 - While avenging Sara's death, Michael learns that Gretchen did not kill her as he thought. Michael also learns the truth about Whistler, that he has secretly been working alongside Mahone to take down the Company. A Company operative takes Whistler's life shortly after this. Sona has burned down and Sucre, Bellick, and T-Bag have escaped during the chaos. After returning to Chicago to look for Sara, Michael is arrested and recruited by Donald Self (Michael Rapaport), a Department of Homeland Security agent, to help bring down the Company in exchange for his freedom. Lincoln, who was arrested in Panama is transferred to Chicago, and along with Mahone, Sucre, and Bellick a deal is made. Also joining the group are Sara, who escaped from Gretchen which resulted in Gretchen's own captivity by the Company, having failed to secure a valuable item, and Roland (James Hiroyuki Liao), a hacker who was assigned to help them after getting arrested for identity theft. Together, they devise a plan to retrieve Scylla, thought of as the Company's 'little black book', from the Company that will help to destroy them. In the meantime, Wyatt (Cress Williams), an agent from the Company, attempts to track Michael and Lincoln down and T-Bag heads North to the US with the "Birds" book in his possession. Michael also begins to experience some troubling health problems.