Dan Evans (Christian Bale), an impoverished rancher and Civil War veteran, awakens to find his barn in flames, set ablaze by two men working for Glen Hollander, to whom Evans owes money. The next morning, as Evans and his two sons herd, they stumble upon outlaw Ben Wade (Russell Crowe) and his gang using Evans' cattle as a road blockade to ambush an armored stagecoach. As he loots the stage, Wade discovers Evans and his two sons watching from the hills. Acknowledging that they pose no threat, Wade takes their horses telling Evans that he will leave them tied up on the road to Bisbee.


Wade travels with his gang to the town of Bisbee, Arizona to enjoy a celebratory drink at the local saloon. Meanwhile, the railroad guards find Evans and his sons with Byron McElroy (Peter Fonda), a Pinkerton agent and lone survivor of the ambush. Evans reveals Bisbee as Wade's likely destination, where the guards immediately return, joined by Evans and McElroy. While Doc Potter (Alan Tudyk), the local medic/veterinarian, treats McElroy, Evans tries negotiating with Hollander, who reveals his intentions to sell the land to the railroad rather than grant water rights to Evans. Enraged at the loss of his livelihood, Evans tries confronting Hollander in the nearby saloon where he finds Wade, whom he distracts long enough for the railroad guards to ambush and arrest him.


The coach's owner, Grayson Butterfield (Dallas Roberts), enlists McElroy, Potter, Tucker (Kevin Durand), one of Hollander's guards, and Evans, who agree for a $200 fee to deliver Wade for arrest. From Evans' ranch, McElroy arranges a decoy wagon to distract Wade's gang, now led by the sociopathic Charlie Prince (Ben Foster), while the real convoy charts a course for Contention, where Wade will be put on the 3:10 P.M. train to Yuma Territorial Prison. As the group prepares to ride out, Evans' older son William (Logan Lerman) demands to accompany them. Evans flatly refuses.


During the journey, Wade kills Tucker during his sleep with a fork stolen from Evans' house, and later McElroy (the former for claiming his horse and the latter for insulting his mother) but is stopped from escaping by the surprise arrival of William, who had followed the group all the way from the ranch. While taking a shortcut through a canyon, the group is attacked by Apache warriors. Evans is wounded but Wade saves him, arms himself, and kills the attackers. Following the shootout, Wade escapes to a Chinese laborer construction camp blasting a tunnel through the mountain range, where the foreman captures and tortures Wade for having killed his brother. Evans, William, Potter, and Butterfield appear and after unsuccessful attempts at negotiation, Potter leads an attack on the foremen and his miners, freeing Wade. As they flee on their horses, Potter is shot and killed, while Wade and Evans destroy the tunnel behind them with dynamite. The group arrives in Contention several hours before the train's scheduled arrival and check into the bridal suite of the hotel, where they are soon joined by several local marshals hired by Butterfield.