A drifter and his slow-witted pal try to make their way in the West.

George Milton and Lennie Small, itinerant farm workers, escape a posse and hop a freight bound for the San Joaquin Valley where they hope to find work. On their way, they spend the night at a thicket along the Salinas River, and there George daydreams about buying a little farm of their own. George's dream, however, is continually endangered by Lennie, a simple-minded giant whose actions have set the posse on their trail. Before they leave, George tells Lennie that if he ever gets in serious trouble, he should return to the river. The pair continue on to the Jackson ranch, where they find work. There, Lennie incurs the enmity of Jackson's son Curley, a stunted bully who detests big men. Candy, an aged and decrepit swamper at the ranch, befriends the two newcomers and warns them to stay away from Curley's bride Mae, of whom Curley is insanely jealous. Later, George confides his dream to Candy, who offers to contribute his life savings to the farm. Just as their dream is on the verge of becoming a reality, Curley goes on the war path over his wife and, in a jealous rage, begins to pummel Lennie. After first retreating in terror, Lennie crushes Curley's fist in his huge hand. That Saturday night, while most of the ranch hands are in town, Mae comes upon Lennie, George and Curley in the quarters of Crooks, a crippled black stable boy, and deduces that it was Lennie who crushed her husband's hand. Mae taunts Curley about it, and in revenge, he orders her to pack her bags and get out. She does so the next afternoon, stopping at the barn to take a puppy that ranch hand Slim had given her. There, she sees Lennie brooding over the body of his own puppy, which he unintentionally killed with his brute strength. They begin to talk and Mae, sensing Lennie's desire to stroke soft things, persuades him to run his fingers through her hair. When she tells him to stop, he panics, causing her to scream. Lenny puts his hand over her mouth to quiet her, and when he removes it, she is dead. Remembering George's words, Lennie flees to the thicket by the river. When Curley organizes a posse to look for Lennie, George steals a pistol and beats the posse to the river, where he finds Lennie waiting. Determined to save Lennie from the mob, George instructs him to look across the river as he describes their farm. As Lennie listens with glee, George puts his pistol to the back of his friend's head and shoots him dead.