The book is set in Soledad, California, sometime during the 1930s. Almost the entire population is suffering from poverty and are desperate for employment, food and income. We are introduced to Lennie Small and George Milton: two men dressed almost identically. George is small and intelligent; Lennie is large mentally slow. His dialogue and actions suggest he suffers from a mental disability.

Lennie starts drinking from a pool of dirty water, resembling a horse. George firmly tells him to stop, demonstrating their dynamic relationship. Lennie behaves like a child, and George takes a parental role. George reminds Lennie about what their plans are: they are going to a ranch where they can undertake work for 50 dollars a month. George also reminds Lennie the reason why they lost their previous employment: he hints that Lennie petted a woman's soft, red dress. Lennie seems to like to pets things too hard and too long - a habit that keeps resulting in dead rabbits.

George continues to verbally swat Lennie when he discovers Lennie was keeping a dead mouse (that he had petted too hard) in his pocket. Then Lennie is disappointed to find out he cannot have ketchup with his beans. He threatens to go live by himself in a cave; George says that would be great as he could enjoy his life independently.

Lennie is visibly upset by this remark. George resolves the argument by telling him his favourite story about where they have their own ranch and Lennie gets to tend rabbits. Finally, George reminds Lennie to return to this exact location by the river if something bad happens.

The two companions arrive at the ranch. They enter the bunkhouse, where they meet an elderly man called Candy. He is missing a hand and is accompanied by a very old dog. Candy explains the ins and outs of the ranch. The boss arrives and questions George and Lennie about their past. Unsurprisingly, George takes the lead and does all the talking. The boss finds it this suspicious and questions their relationship. George lies and says he and Lennie are cousins, and that their last employment ended because it was done. The boss leaves.

The boss' son arrives. Curley is a small man but appears arrogant and conceited, as he immediately tries to intimidate George and Lennie. He tries to initiate an argument with Lennie, but George interferes. Curley tries to appear unfazed, but leaves.

Candy explains that Curley got his name from his curly hair. He used to be a lightweight fighter and now likes to assert his dominance by starting fights with larger men. Candy says this behaviour has worsened since his married a "tart," who has "the eye" for every man nearby. Curley wears a glove of Vaseline to "keep his hand soft for his wife." Candy leaves.

George warns Lennie to avoid Curley. Also, he once again reminds Lennie to return to the river if anything bad happens. Coincidentally, Curley's wife then enters the bunkhouse, looking for her husband. Lennie struggles to take his eyes off the nameless woman. Slim, the "prince of the ranch", arrives and sends Curley's wife on her way. Slim is practical, tough, empathetic and highly skilled at his job as a jerkline skinner. Lennie is warned to avoid her. Lennie says he doesn't like the ranch - but they must remain there until they can buy their own.

Carlson arrives asking Slim about his new litter of puppies. He suggests giving one to Candy to replace his ancient dog. Lennie becomes exciting at the thought of puppies. Finally, Curley returns looking for his wife.

George and Slim arrive at the bunkhouse. He thanks Slim for Lennie's new puppy. Slim questions George's relationship with Lennie, wanting know why George travels with a "cuckoo" like Lennie. George explains that he knew Lennie's Aunt Clara. He admits he used to tease Lennie, until he appreciated his companion's endless loyalty. He believes Lennie isn't crazy, just lacking intelligence. He explains that he had gotten used to Lennie's behaviour, and had seen similar men suffer from loneliness. As a result, they travel together. George proceeds to tell Slim what happened in Weed with the girl in the red dress. We discover she became terrified as Lennie petted her cried rape as Lennie petted her soft attire. They had to run and hide from those seeking revenge.

Carlson arrives and continues complaining about Candy's old dog. He offers to shoot the companion with his Luger. Candy is devastated at this idea. Surprisingly, Slim sides with Carlson, arguing that he would want to be shot if he were the dog. Candy appears defeated as he lies on his bed and stares at the ceiling. Carlson takes the dog outside. George tries to ease the tension by pretending to play cards. However, the bunkhouse is silent and hideously tense. Finally, a shot is heard, and Candy turns his face to the wall.

Crooks arrives at the bunkhouse. He is responsible for all of the horses and has his own private room. He lives a secluded life because he is black. Crooks tells Slim that Lennie is with the puppies and worries that is is petting them too much. Slim goes to take a look.

Whit, another ranch hand, starts a conversation with George about Curley's wife. He calls her a "loo loo." They agree and say Curley's pants are "just crawlin' with ants," hinting at his intense sexuality. Whit invites George to attend the local brothel with them on Saturday night.

Lennie, Carlson and Curley arrive. Curley finds out that Slim is in the barn and immediately assumes he is having an affair with his wife and storms off to find out. Whit and Carlson follow, hopeful for a fight.

Lennie asks George to tell him the story about their dream again. Candy overhears and offers to contribute 300 dollars if he can live at the farm too. They all imagine what life will be like once they have a place of their own. Candy becomes upset about his dog and admits he should have shot his companion himself.

All the other men return, and the atmosphere intensifies. Slim is offended that Curley has accused him of being attached to his wife. Carlson calls Curley a coward. Curley starts punching Lennie, who does not react until George tells him to. Lennie grabs Curley's hand and crushes it. Slim ends the fight and tells Curley to say he got his hand caught in a machine. He warns him that if he tries to get Lennie fired, he will tell everyone about his defeat. Lennie worries that he has done a "bad thing" and won't be able to tend the rabbits. George reassures him that this is not the case.

Crooks is in his room when Lennie arrives. Crooks has his own private room because he is black, resulting in him being mistreated by everyone else. The other men have gone to Suzy's brothel. Lennie immediately tells Crooks about his dream farm. You'd expect Crooks to relate to Lennie, both being outcasts. However, loneliness has made Crooks hostile, and he starts taking his anger out on Lennie by suggesting that George has abandoned him. Lennie panics and gets mad. Lennie towers over him, but Crooks quickly retracts his hurtful comments.

Crooks then tells Lennie he believes every man needs another man to confide in. Candy arrives and joins in the conversation. Crooks wants to be a part of the plan.

Curley's wife then appears in the doorway. She claims that all the weak people were left behind. She reveals she suffers from loneliness and is in desperate need of someone to talk to. She asks Lennie how he got the bruises on his face. Crooks tells her to leave, but she threatens to have him lynched.

The other men return from their trip to the brothel. When George arrives, Candy admits they've told Crooks about the farm. George is furious. Crooks then retracts his request to join in the plan and retreats once again to the sadness of his solitary life.

Lennie is alone in the barn. He is petting a puppy, but has done it too long and hard. He is unsure what to do with the dead body. First, he covers it with hay. Next, he flings it across the barn. He doesn't seem to be distressed about the puppy's wellbeing, but instead is worried that George won't let him tend their future rabbits.

Curley's wife arrives. She offers some advice and tells him not to feel bad as there are plenty of dogs in the world. Lennie confides in Curley's wife, explaining how petting things gets him into trouble. Curley's wife describes how soft her hair is, and tells Lennie to feel it. He enjoys it so much, he starts petting it harder. Curley's wife panics and tells him not to mess it up. He eventually breaks her neck.

Lennie really panics that George really might not let him tend the rabbits this time. He recalls George's instruction about what to do if something bad happens. He returns to the river, taking the dead puppy with him.

Candy discovers Curley's wife's body. He decides to find George to inform him about his companion's actions. They both know they should turn Lennie in, but he'll either be imprisoned or killed by Curley. Candy questions the future of their farm. George admits his he knew they'd never achieve their dream, but tried to pursue it to please Lennie.

Candy is surprised at Lennie's fatal actions, since he believed Lennie was a nice man. George explains that he didn't intentionally kill her. George decides the best thing to do is act oblivious to the death so the men wouldn't suspect him of being involved. They agreed that George should return to the bunkhouse, where Candy will come running in a minute later with the news of his discovery. As George leaves to put the plan into action, Candy becomes teary over the realisation that his dream farm is gone. Candy then starts shouting at the corpse of Curley's wife, stating that she intentionally caused the fatal events.

All the men go to look at the dead woman. Curley immediately blames Lennie and announces he intends to shoot him in the guts. Curley and Carlson collect guns and men to join this mission. Slim quietly tells George that Lennie could have been to blame. George remains quiet, and Slim reminds him about their history in Weed. George says nothing.

George strategically tells the men that Lennie would go south. George tells Slim perhaps he could bring Lennie back, so he could be imprisoned rather than murdered.

Curley gives each of his men a task to complete. Carlson is to shoot Lennie in the guts. Whit is to go to Soledad and get the deputy sheriff. George is to join the search party for Lennie.

Lennie sits near the river, waiting for his companion. He's starts to think about how much trouble she causes George and decides if George is to leave him, he will go away. He then starts to think of his dead Aunt Clara. He imagines his relative accusing him of never considering George. She then starts describes the life George could have without Lennie to care for. She then disappears, only to be replaced by a very large and angry rabbit. The rabbit scoffs at Lennie's dream of tending the rabbits. He then suggests that George will beat his companion and leave him for good. Lennie covers his ears and cries out for George.

Lennie is thrilled to discover George appearing from the brush. Lennie begs him to punish him so they can return to normal sooner. George refuses to give him hell, but instead remains quiet. Lennie asks George to recite the story about their dream again. George takes out Carlson's Luger . He can hear Curley and the other men approaching.

George recites the story and Lennie adds the usual details about ending the rabbits. George tells Lennie to keep looking across the river while he tells the story. As Lennie looks over the bank, envisioning his dream farm and rabbits, George puts the gun to the back of his companion's head and pulls the trigger. Lennie lies dead in the sand.

The approaching men hear the shot and come running. They believe Lennie had the gun and that George took it from him. However, Slim understands exactly what has happened. He approaches George and offers words of reassurance.

The men question George about what happened, but Slim intervenes. He invites George for a drink, and reassures him that he made the right decision. They both leave. Carlson looks at the others and questions what the two men are discussing.