In Arizona in the late 1800s, infamous outlaw Ben Wade and his vicious gang of thieves and murderers have plagued the Southern Railroad. When Wade is captured, Civil War veteran Dan Evans, struggling to survive on his drought-plagued ranch, volunteers to deliver him alive to the "3:10 to Yuma", a train that will take the killer to trial.

Depression-era bank robber John Dillinger's charm and audacity endear him to much of America's downtrodden public, but he's also a thorn in the side of J. Edgar Hoover and the fledgling FBI. Desperate to capture the elusive outlaw, Hoover makes Dillinger his first Public Enemy Number One and assigns his top agent, Melvin Purvis, the task of bringing him in dead or alive.