The story begins with George and Lennie arriving at a small pond after a long day’s walk, where they rest before heading to the nearby ranch where they are contracted to start work. George discovers that Lennie has been keeping a dead mouse in his pocket, stroking it as he walked. George makes Lennie throw the mouse away, and then to keep him from getting too sad, tells him the story of their dream – how they’ll save enough money, a “stake”, to set themselves up on a small independent farm. Lennie becomes particularly excited when George comes to his favorite part of the story – the part where Lennie gets to take care of the farm’s rabbits. Conversation also reveals Lennie’s history of violence and George’s resentment that his life is dominated by watching out for him.

The next day, Lennie and George start at the ranch, where they are introduced to the boss, old-timer Candy and his elderly dog, respected lead hand Slim, ranch hands Carlson and Whitney, the boss’s arrogant son Curley, and Curley’s flirtatious wife. Conversations reveal that the short-tempered Curley is always looking to pick fights, that his wife is a flirt, that Slim’s dog has just had a litter of pups, and that Carlson dislikes Candy’s aged dog and is eager to have him put down. As everyone goes to dinner, George and Lennie linger, with George warning Lennie not to say anything that might antagonize Curley, and adding that if he (Lennie) behaves, he might be able to adopt one of the pups.

That night, Lennie brings one of the pups to the bunkhouse, and George tells him angrily to take it back to the barn. After he goes, George tells Slim some of Lennie’s history – how he and George had to leave the town where they were previously working because Lennie scared a girl when he touched her dress. Meanwhile, Carlson convinces Candy that it’s time to put his dog down, and Candy allows him to take the dog out and shoot it. After Slim goes out to help with the horses and after Lennie returns, conversation between George and Lennie about their dream farm leads Candy to offer his savings to help them buy it, as long as he can come and live with them. George agrees. Shortly afterwards, Curley comes and picks a fight with Lennie, who becomes frightened, grabs his fist, and crushes it to a pulp. Everyone agrees to keep secret what happened.

The next day, Lennie is in the barn mourning the death of his pup, which he accidentally killed when he tried to discipline it. His grieving is interrupted by the arrival of Curley’s wife, who complains that she’s lonely and then tells Lennie stories about how badly she’s been treated all her life. She also lets him touch the softness of her hair, but becomes scared when he holds too tightly to it. In his efforts to calm her down, Lennie accidentally kills her, and then flees, afraid of what George will say. When the body is discovered, everyone (including George) realizes that she was killed by Lennie. Curley leads the men on a search, vowing to shoot Lennie on sight. George heads out on his own and finds Lennie sitting quietly by the pond where they rested before traveling to the ranch. Lennie apologizes for making George angry, but George tells him everything’s all right, and then starts telling him the story of the farm. As Lennie is becoming increasingly happy, George pulls out Carlson’s gun and shoots him. Curley and the others come running and are glad that Lennie is no longer a danger, but only Slim realizes just what George has done, and he takes him for a quiet, private drink.