George Milton and Lennie Small, two itinerant workers from Auburn, California, make their way across the state’s harsh landscape on their way from one ranch job to another. As they close in on a job just outside the town of Soledad, they stop for the night at a pool off the Salinas River to enjoy one last night of freedom. As they prepare dinner and form a plan for their arrival at the ranch, the dynamic between the men becomes clear: George is a sharp, wiry man with dreams of saving enough money to buy land for a farm and become the master of his own destiny. Lennie is a hulking but simple-minded man who has short-term memory problems and a fascination with stroking soft objects. This habit has resulted in both George and Lennie (who have traveled everywhere together since their youth) being chased out of Weed, the town where their last job was, after Lennie grabbed the soft hem of a woman’s skirt in order to feel the fabric. George feels burdened by Lennie, but knows he must keep the man with him if they’re both to survive. He tells Lennie that if Lennie should ever get into any trouble at their new ranch, he should return to this very spot and hide in the brush until George comes for him. They drift off to sleep as George tells Lennie about how their future will be, describing the lush, secluded farm with its vegetable garden, animal pen, and best of all, a hutch full of soft rabbits for Lennie to pet.
The next day, the men arrive at the ranch. Candy, an elderly swamper missing a hand, shows them to the bunk house where they’ll sleep alongside the other laborers. The boss of the ranch comes to greet the men and agrees to allow them to stay on, though he’s disappointed that they’re late for their shift and skeptical of two men who travel together. Candy fills George and Lennie in on the dynamics of the ranch, warning them that the boss often takes his anger out on the black stable hand, Crooks, while the boss’s son Curley, a short and pathetic man, is always desperate for a fight in which he can prove his strength. Candy also mentions that Curley’s new wife has “the eye,” and is constantly hanging around the laborer’s quarters trying to flirt with the ranch hands. Sure enough, when Candy steps out to ready the wash basins and tend to his elderly dog, Curley’s wife pokes her head into the bunk house, gives Lennie and George the once-over, and asks where Curley is. Another laborer named Slim, a mule driver, enters the bunk house and shoos Curley’s wife away. As Slim introduces himself to George and Lennie, he, too, expresses his surprise at two men sticking together as they travel around. As the other ranch hands, Carlson and Whit, come in to wash up, they ask Slim about his dog’s new litter of puppies. Lennie becomes excited, and Slim tells him that he can have one. Curley comes by the bunk house, fuming and in search of his wife. After Curley leaves, George tells Lennie that he’s worried about trouble with Curley.
That evening, after dinner, the men enjoy some leisure time. George and Slim play cards in the bunk house while some of the other laborers play a game of horseshoes outside. Lennie is in the barn, playing with the new puppy Slim has given him. George thanks Slim for his generosity and explains that he has been looking after Lennie ever since Lennie’s Aunt Clara, his former caretaker, passed away. George vents his frustrations about traveling with Lennie and even tells Slim about their troubles in Weed. The horseshoe game ends and the other men come into the bunk house. Candy brings his dog inside, and Carlson comments on the dog’s disgusting odor. He suggests Candy put the dog, who is blind, lame, and mangy, out of its misery. Carlson offers to shoot the dog with his pistol, and Slim promises Candy a new puppy from the litter. After much persuading, Candy reluctantly agrees. Carlson takes the dog outside, and soon the others hear the sound of a gunshot. Crooks enters the bunk house and beckons Slim to the barn to help care for a mule with a bad hoof. After Slim leaves, Whit invites George to come along to a whorehouse the following night. George replies that he’s trying to save his money. Carlson and Lennie return to the bunk and crawl into their beds. Curley comes by looking for his wife—he is suspicious to see everyone in the bunk house except Slim and goes out to look for him. Carlson and Whit follow him, hoping for a fight. Lennie asks George to tell him about their farm, and George gets lost in his own reverie as he talks aloud about their little plot of land. Candy interjects to tell them that he can help make their dream a reality if they’ll let him join them on the farm—he’ll pitch in the money he has saved up from the accident that cost him his hand. The rest of the men return to the bunk house. Slim and Curley are in the midst of an argument when Curley spies Lennie smiling, still lost in daydreams of the farm. Curley begins hitting Lennie, but Lennie refuses to fight back even as Curley bloodies his face. George orders Lennie to stand up for himself, so Lennie seizes one of Curley’s hands and crushes it. Slim urges Curley to tell everyone he’s gotten his hand crushed in a machine, warning him there will be trouble if he tries to get Lennie and George fired. Curley agrees. The other men hurry Curley away to the hospital. George assures Lennie that he's done nothing wrong.
The following night, the men are in town visiting billiards halls and whorehouses. Lennie plays with his puppy in the barn for a while and then pays the stable hand, Crooks, a visit in his room, which is separate from the bunk house and just off the stable. Crooks claims that he doesn’t want Lennie’s company—just as he isn’t allowed to fraternize with the white ranch hands, he doesn’t want any of them coming into his space. But when he sees how innocent and well-meaning Lennie is, he agrees to let the man in. As Crooks tells Lennie about his painful past marked by racism, discrimination, and loneliness, Lennie seems not to understand the gravity of anything Crooks is telling him. Crooks continues talking to Lennie and asking him questions, but when Crooks asks Lennie what he would do if George never came back from town, Lennie becomes confused and angry. Crooks apologizes for scaring Lennie, and insists he was just trying to get Lennie to understand his own loneliness. Lennie tells Crooks about his and George’s plan to buy a farm, and Crooks tells Lennie that while every man who passes through the ranch has dreams of his own land, not one of them ever gets it. Candy comes to the doorway looking for Lennie, and Crooks invites Candy to come in and sit down. Candy and Lennie discuss their plans for a farm, but Crooks predicts their dream will never come to fruition. Curley’s wife comes to the door, claiming to be looking for Curley, though she quickly admits that she knows he’s in town and is simply looking for company. Crooks urges Curley’s wife to leave, claiming she’ll only cause them trouble. Curley’s wife notes Lennie’s bruises and thanks him for beating Curley up. Crooks orders Curley’s wife to leave. She turns on him, threatening to have him lynched if he speaks to her again. She leaves the barn after thanking Lennie again for roughing Curley up. Crooks tells Lennie and Candy to leave, and though Candy tries to comfort the clearly-shaken Crooks, Crooks admits that what Curley’s wife said was true—she could have him murdered at any time. George comes to the doorway—all the men have returned from town. He asks Lennie to come with him back to the bunk house, and they leave together. Candy leaves, too, and Crooks is alone once again.
The next afternoon, Lennie is in the barn alone while the men play horseshoes outside. He holds his puppy in his hands—he has accidentally killed it by hitting for nibbling at his fingers. Lennie is angry at the puppy for dying, and worries that if George learns what has happened, he won’t let Lennie tend rabbits in the future. Curley’s wife comes into the barn and approaches Lennie. When she sees that the puppy is dead, she tries to soothe Lennie by assuring him he’ll be able to get another one. Lennie tells Curley’s wife he isn’t supposed to be talking to her. She laments her unending loneliness, and states that she should have had a different life—she says she should have been a movie star. Lennie doesn’t seem to comprehend anything she’s saying, and instead continues worrying aloud about his rabbits. Curley’s wife asks Lennie why he’s obsessed with rabbits, and he replies that he likes to touch soft things. Curley’s wife says she, too, likes the feeling of soft things, and offers to let Lennie stroke her soft curls. Lennie begins stroking her hair, but when his touch becomes too rough, she screams for him to stop. Frightened, Lennie puts his hands over her nose and mouth. When she continues screaming, he shakes her until her neck snaps. Realizing what he’s done, Lennie pushes some hay over Curley’s wife’s body and runs away for the pond to wait for George. Candy comes into the barn looking for Lennie and discovers Curley’s wife’s body. He fetches George, who looks with horror upon the mess Lennie has left. Realizing their dreams of a farm are shattered and that the other men will kill Lennie when they realize what he’s done, Candy and George quickly devise a plan that will keep George from looking suspicious. George returns to the bunk house, and Candy goes out to tell the other men what he’s discovered. As Candy brings all the men—including Curley—into the barn, Curley orders Carlson to fetch his gun so that they can hunt Lennie down and kill him. Carlson goes to the bunk house, but returns without his gun, claiming Lennie has stolen it. George comes into the barn, pretending to see Curley’s wife’s corpse for the first time. He begs Curley to spare Lennie’s life, but Curley remains determined to murder Lennie.
Lennie sits by the pool off the Salinas, worried about getting in trouble with George and tortured by visions of his Aunt Clara, who turns into a giant rabbit and harasses Lennie for his stupidity and cruelty. George comes crashing through the brush and embraces Lennie. Lennie apologizes for what he’s done, but George insists that it doesn’t matter and says he isn’t mad at Lennie at all. As the sounds of the other men’s voices can be heard approaching, George urges Lennie to look out at the river so that he can picture their future on their farm together. George tells Lennie about the vegetables, animals, and rabbits they’ll tend, and Lennie happily looks forward to living “on the fatta the lan’.” As George hears the men’s footsteps approaching, he pulls Carlson’s pistol from inside his jacket, aims it at the back of Lennie’s head, and fires, killing Lennie instantly. The other men arrive at the pool, and Curley thanks George for dispatching with Lennie. George is visibly shaken. Slim tries to comfort him, insisting that he did what he had to do. As Slim helps a nearly-catatonic George back toward the ranch, Carlson and Curley wonder aloud what could be “eatin’ them two guys.”