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.
Elsewhere, 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 Tuscon. 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.
Dillinger is later goaded into a bank robbery job in Sioux Falls by an acquaintance. Even though Baby Face Nelson is involved, whom he doesn't like, and Ed Shouse has arrived to rejoin the gang, Dillinger agrees. A shootout (triggered by Nelson shooting a cop outside the bank) occurs in which Dillinger is shot in the arm, and an acquaintance is shot and left for dead. They retreat to Nelson's wilderness lodge hideout at Little Bohemia, where Dillinger's wounds are treated.
Purvis and his men apprehend the acquaintance (who is still alive) and torture him to find the rest of the gang's location. They arrive at Little Bohemia and Purvis organizes another failed ambush. Dillinger and Red escape separately from Nelson and the rest of the gang. Agent Winstead and another agent pursue Dillinger and Hamilton through the woods on foot, engaging them in a running gun battle in which Red is shot and fatally wounded. After a car chase, Purvis and his men kill Nelson and the rest of the gang, including Shouse and Homer Van Meter (Stephen Dorff).
Dillinger manages to meet Frechette, telling her he plans to do one last job that will pay enough for them to escape together. However, Dillinger drops her off at a hotel he thinks is safe and helplessly watches as she is captured. An interrogator viciously beats Frechette to learn Dillinger's whereabouts, but she refuses to talk; Purvis and Winstead arrive and angrily break up the interrogation. Meanwhile, Dillinger is meeting with Alvin Karpis (Giovanni Ribisi), who tries to recruit a disinterested Dillinger in a train robbery with his associates, the Barker Gang. Dillinger receives a note from Billie through his lawyer, Louis Piquet (Peter Gerety), telling him not to try and break her out of jail.
Through crooked cop Zarkovich, Purvis enlists the help of prostitute and Dillinger acquaintance Anna Sage (Branka Katic), threatening her with deportation if she is not cooperative. She agrees to set up Dillinger, who is hiding with Sage.
That night Dillinger and Sage see a Clark Gable movie called Manhattan Melodrama at the Biograph Theater. When the movie is over, Dillinger and the women leave as Purvis move in. Dillinger spots the police and is shot several times before he can draw his gun. Agent Winstead, who fired the fatal shot, listens to Dillinger's last words.
Later, Winstead meets Frechette in prison. He tells her Dillinger's dying words, which were "Tell Billie for me 'Bye bye Blackbird.'"[citation needed] The closing text reveals that Melvin Purvis quit the FBI shortly afterwards and died by his own hand in 1960, and that Billie lived out of the rest of her life in Wisconsin following her release in 1936.
