The series premiered on Fox in 2005, created by Paul Scheuring. The first season is widely considered a masterpiece of serialized tension, following structural engineer Michael Scofield (Wentworth Miller) as he orchestrates an elaborate plan to rob a bank, get himself incarcerated, and break his wrongly-convicted brother Lincoln Burrows (Dominic Purcell) out of death row. This season consisted of 22 episodes, ending with the iconic, albeit temporary, escape.

The third season (13 episodes), subtitled Prison Break: Redemption , was shortened and altered due to the 2007–2008 Writers Guild of America strike. It relocated the action to a hellish Panamanian prison called Sona, forcing Michael to engineer another escape. By the fourth season (24 episodes, plus a two-part finale titled The Final Break ), the narrative had morphed into a revenge thriller involving a shadowy organization known as "The Company." This season marked the intended end of the series, with a two-hour movie finale providing closure in 2009.

The second season, also 22 episodes, shifted the genre from a prison drama to a manhunt thriller. Titled Prison Break: Manhunt , it followed the escaped convicts as they ran from federal agents, most notably the relentless Agent Alexander Mahone (William Fichtner). While critically acclaimed, the season struggled to replicate the claustrophobic intensity of the first.