George and Lennie are complete opposites; George is small, dark, and smart, while Lennie is a child like baby with a featureless face. However, they are like a family, who are migrant workers moving from place to place looking for work, during the Great Depression as well as the dust bowl. The story begins with the two of them walking into a small clearing with a pond, which George decides is suitable enough to spend the night. Lennie becomes confused as to why they are where they are, and so George reminds him they are going to a ranch to look for work. George then realizes Lennie is hiding something from him, and begins questioning him until he finds out Lennie is holding a dead mouse. He throws it away, then asks Lennie to find wood to start a fire to cook their food. Lennie returns with a single stick and the mouse, which George once again takes away. George then cooks the food and tells Lennie about the dream they have to own their own land with a rabbit patch before getting ready to sleep.
The next afternoon they arrive at the ranch and are shown their accommodations by Candy, the old swamper. The boss then interrogates Lennie and George about their absence from that morning, as well as their motivation to work on the ranch. After the boss leaves, his son Curley walks in and begins sizing up the new workers. After he leaves, George warns Lennie to go back to the pond if anything bad happens, when they realize Curley's wife is in the bunkhouse. She begins asking the whereabouts of her husband, when the cowhands begin entering the building. She hears that her husband is going back to their house, and quicly leaves, when Slim, the jerkline skinner, introduces himself to George and Lennie. Soon after Carlson, a ranch hand, begins trying to convince Slim to get Candy to shoot his dog and replace it with a puppy from his dog's litter. The ranch hands the leave for supper, when Curley pops in and begins inquiring where his wife is.
The following afternoon, George and Slim begin talking about he and Lennie's past, including the incident with Lennie and the girl in Weed. Just as they finish up the conversation, Lennie walks in and sits on his bunk. George kicks him out after he discovers Lennie is trying to sneaking in a puppy, when Candy and Carlson enter the bunkhouse. Carlson finally convinces Slim to help him get rid of Candy's dog, and so he leaves with the dog and his gun. A few moments later, the gunshot goes off, and Slim leaves to put tar on a mules foot. Lennie and Carlson return, and suddenly Curley enters asking about his wife again, as well as where Slim is. All the ranch hands leave except Candy, George, and Lennie to see if there will be a fight, and so George tells Lennie about their dream again. Candy overhears this, and begins asking if it would be possible for him to join them. The other ranchers begin entering the bunkhouse again, and Candy tells George that he feels guilty he wasn't the one who shot his dog. Curley is with them, and the ranch hands are bothering him about keeping control of his wife when he sees Lennie smiling in the corner. Curley picks a fight with him that results in his hand being crushed by Lennie, and being told by slim that he "caught it in a machine".
The following night, all the men have went into town except Lennie, Candy, and Crooks, the stable buck. Lennie wanders into Crooks room, he reacts grumpily to him until he realizes Lennie isn't very smart. He then manipulates him by saying that George may never return, just to try to get him to imagine how lonely he feels since he is black. Candy eventually wanders in and begins talking about a plan he has for the small plot of land. Crooks begins asking if he can join them, when Curley's wife walks in and begins threatening crooks. The other cowhands return, and George finds Candy and Lennie and takes them out of crooks' room.
The next morning, Lennie is in the barn trying to hide the body of his pup he accidentally killed in the hay. Curley's wife walks in and begins talking to him, then sees the dead puppy. She begins talking about her dreams of becoming an actor, and the events leading up to her marriage to Curley. She then asks him why he loves rabbits so much, and he tells her he loves how soft they are. She then tells him she has really soft hair, and lets him stroke it. However, he begins to mess it up, and so she becomes hysteric, which leads Lennie to accidentally snap her neck to make her quite. He shortly after realizes she is dead, and flees the scene thinking he will be in trouble. Candy and George find the body, so George has Candy tell the other ranchers Lennie killed him to throw off any suspicions. While the cowhands plan to get their revenge, George grabs Carlson's gun and throws them off Lennie's trail.
Lennie arrives at the pond where George told him to hide if he got in trouble, and begins having visions of a rabbit. The rabbit is warning him that George is mad at him, and suddenly his vision turns into his aunt Clara giving him trouble for ruining George's life. George then stumbles into the clearing and begins calming Lennie. He tells Lennie to look out across the pond, and begins telling him about their dream one final time. At the ending of it, George shoots Lennie in the back of the head, which alerts the other ranchers where he is. Slim then tells George it was the only option, and brings him back to the bunkhouse for a drink.