A random cross-section of 1880s American society boards the stagecoach from Tonto, Arizona Territory, to Lordsburg, New Mexico Territory, including the alcoholic Doc Boone (Thomas Mitchell), whiskey salesman Samuel Peacock (Donald Meek), the pregnant officer's wife Lucy Mallory (Louise Platt), gambler and Southern Gentleman Hatfield (John Carradine), banker Henry Gatewood (Barton Churchill), and soiled dove Dallas (Claire Trevor). US Marshal "Curley" Wilcox (George Bancroft) provides protection, and Buck (Andy Devine) drives the coach. Before long, they pick up the Ringo Kid (Wayne), who is planning to kill the outlaws who killed his family. Wilcox and the Kid are old friends, but Wilcox arrests him anyway. The Kid begins to fall for Dallas.
The US cavalry warns the stagecoach passengers that Apaches are active in the area and that Geronimo is on the warpath. However, the stagecoach sets out anyway, first with a full cavalry detachment, but not long on the trip they break away to join the main Army group. They get to Dry Fork without incident, though the outpost is undefended, and continue on to Apache Wells, where Lucy is expecting to meet her husband, who is in the Army. When they reach Apache Wells, they find it nearly abandoned, no soldiers in sight, and Lucy's husband nowhere to be found. Someone at Apache Wells tells Lucy that her husband has been wounded, and hearing this Lucy faints and gives birth, off-screen, so the passengers rest a day before pressing on. The Ringo Kid considers escape, but decides against it when he sees smoke from buildings burnt by Apaches. They continue on to Lee's Ferry, which is burnt down, and ford the river. They think they're clear, but several dozen Apaches on horseback attack them. After a long chase, during which one passenger dies and another is injured, the US cavalry stages a last-minute rescue.
Once they arrive in Lordsburg, the Ringo Kid has a shoot-out with the outlaws, then goes back to Wilcox, expecting to be arrested. Instead, Wilcox and Doc Boone laughingly allow the Kid to escape with Dallas, and they ride off into the sunrise.