The film opens in 1933 as John Dillinger (Johnny Depp) is brought to the Indiana State Prison by his partner John "Red" Hamilton (Jason Clarke), under the disguise of a prisoner drop. Dillinger and Hamilton overpower several guards and free members of their gang including Charles Makley (Christian Stolte) and Harry Pierpont (David Wenham). The jailbreak goes off without a hitch, until gang member Ed Shouse (Michael Vieau) beats a guard to death. A shootout ensues as the gang makes its getaway. Dillinger's friend and mentor Walter Dietrich (James Russo) is killed, and a furious Dillinger kicks Shouse out of the car. The rest of the gang retreats to a farm house hideout, where crooked Chicago cop Martin Zarkovich (John Michael Bolger) convinces them to hide out in Chicago, where they can be sheltered by the Mafia.
In East Liverpool, Ohio, Melvin Purvis (Christian Bale) and several other FBI agents are running down Pretty Boy Floyd (Channing Tatum). Purvis kills Floyd and is promoted by J. Edgar Hoover (Billy Crudup), who is struggling to expand his Bureau into a national police agency, to lead the hunt for John Dillinger, declaring the first national "War on Crime."
In between a series of bank robberies, Dillinger meets Billie Frechette (Marion Cotillard), his love interest, at a restaurant, and proceeds to woo her by buying her a fur coat. Frechette falls for Dillinger even after he tells her who he is, and the two quickly become inseperable.
Melvin Purvis leads a failed ambush at a hotel where he believes Dillinger is staying. An agent is shot and killed by the occupant. After the man escapes, Purvis realizes the killer wasn't Dillinger but Baby Face Nelson (Stephen Graham). After this incident, Purvis demands that Hoover bring in professional lawmen who know how to catch criminals dead or alive, including Texas "cowboy" Charles Winstead (Stephen Lang).
Police finally find Dillinger and arrest him and his gang in Tucson. Dillinger is extradited back to Indiana where he is locked up pending trial. Dillinger and a few inmates escape. Dillinger is unable to see Frechette, who is under tight surveillance. Dillinger learns that Frank Nitti's (Bill Camp) Chicago Outfit associates are now unwilling to help him; Dillinger's crimes are motivating the U.S. government to begin prosecuting interstate crime, which imperils Nitti's lucrative bookmaking racket
