Lennie and George are best friends traveling together in search of work on northern California farms. These two are flat broke – as in, "not even any quarters in the couch" broke. This is not good, as they have a dream of owning their own idyllic farm someday. George is the "brains" behind this operation – a smart guy who does all the talking when it comes to finding and keeping work. Lennie is physically strong, yet mentally slow. While both George and Lennie are good workers, they can’t hold down jobs for long due to Lennie's childlike mentality and odd fetish for petting things, which includes mice, rabbits, puppies, and…women. (This last one, of course, being the biggest issue).
Good fortune (of sorts) smiles upon them briefly when they get work at a ranch near Soledad, California. The night before they begin the new job, they hang out in a grove together where George points out a safe spot where Lennie should go if he ever gets in trouble. George and Lennie meet some of the other co-workers including Candy (an old, one-handed fellow who owns a smelly dog), Crooks (a lonely stable hand), and Curley (an unfaithful man with severe anger management problems). Curley is the ranch boss's son and a hotheaded little guy who used to fight in the featherweights. Curley clearly has something to prove, and seems to want to prove that something to Lennie. George warns Lennie to stay away from Curley, though he says if Curley picks a fight, Lennie should fight back.
We learn that Curley also has a new wife, whom no one is allowed to look at (which is difficult, because she quite likes male attention). Though most of the men know to stay clear of Curley's wife, Lennie innocently enjoys her flattering attentions. George warns Lennie to steer clear of her.
Back at the ranch, we meet Slim, our local and wise ranch demi-god. We see Carlson, a callous ranch hand, who notes that Slim’s dog has had some new puppies. He suggests Candy adopt one of Slim’s puppies and shoot Candy’s old dog, primarily because it’s smelly.
Then two amazing things happen at once. First, Friday comes around, and Slim earns George’s confidence. George admits that he and Lennie ran away from their last job in Weed, California because Lennie had tried to pet a woman’s dress and she accused him of rape. Second, Carlson gets Slim to give up a pup in return for Candy’s dead dog. Candy reluctantly gives in, but cannot bring himself to shoot his beloved dog, so Carlson does it for him.
Slim then goes out to the barn to do some work on a mule. Curley follows, searching for his wife, paranoid that Slim might be with her. Lennie and George are left to discuss their dream farm, and Candy perks up, overhearing. George hesitates a little but then lets Candy in on the dream. The men agree to go in on the farm together. Meanwhile, Candy says he should’ve shot his dog himself, like a real man.
Curley, cowed, follows Slim into the bunkhouse and, embarrassed, has the feeling of "sorry I thought you were having sex with my wife." Curley’s itching for a fight to make him feel better, and quickly pounces on Lennie. George insists that he fight back on his own, so Lennie crushes Curley’s hand. As the men minister to Curley, Slim casually suggests to him that if he tries to get Lennie and George fired, he’ll be the laughingstock of the ranch for having lost the fight. So Curley tells everyone he got his hand caught in a machine.
Saturday night, universally the time for drunken visits to the whorehouse, opens with Slim and Lennie alone at the ranch with Crooks, the black stable hand. Lennie shows up in Crooks’s private (that is, segregated) little room. Crooks slowly warms up to Lennie’s company, moved by how dense and earnest the man is. Hearing from Lennie about the dream farm, Crooks takes the opportunity to say that the same foolish goal is on the mind of every ranch hand and no one ever follows up on it.
Candy joins the group and helpfully supports Lennie and his dream farm. Crooks begins to soften to the idea. He timidly suggests that if they got the place, and wanted someone around to help out for nothing but room and board, he’d be OK with joining them. Soon after, Curley’s wife enters. She calls the men weak, as they were left behind while the others went whoring (obviously a manly activity, much like shooting your dog). When Crooks tries to get her to leave his room, she explodes, reminding him that he’s a "nigger" and that she could have him "strung up on a tree so easy it ain’t even funny." That ends the party.
On Sunday afternoon, Lennie’s in the barn with a dead puppy. He admonishes the puppy for "going and getting killed," which we think is actually not so much the puppy’s fault as it is Lennie’s. As he tries to cover the creature with hay, Curley’s wife walks into the barn. She gets close to Lennie and describes how she should’ve been a movie star in Hollywood. Hearing that Lennie likes to pet soft things, she offers up her hair as a petting object. She worries about him messing it up though, and as she wriggles to avoid a ruined hairdo, Lennie panics and, again accidentally, breaks her neck and kills her.
Lennie recalls what George said about heading to the grove if he ever got into trouble. Lennie heads for his safe spot in the grove.
Candy discovers Curley’s wife’s body and runs out to George, who identifies it is as classic Lennie handiwork. George hopes they’ll lock Lennie away someplace nice, though Candy points out that they’re more likely to go for a shooting or lynching-type punishment. George admits wistfully that he knew they’d never get the farm of which they had dreamed.
George plans to hear the news with all the rest of the guys and pretend he didn’t know. Candy, left alone with Curley’s dead wife, berates her for costing him his dream and is reduced to lonely tears. By the time Curley finds out, he immediately concludes Lennie was the murderer, and becomes more worked up about shooting Lennie than about having a dead wife.
As Carlson and Curley run off to get their guns, Slim and George have a solemn conference. Slim grimly notes that even if Lennie escapes Curley’s rage, he’s likely to be locked up like an animal in an asylum. Carlson then runs in, announcing his gun is missing. Curley concludes that Lennie, having clearly stolen the gun, is armed and dangerous, which justifies their decision to shoot him. Curley insists that George come with them on the Lennie-hunt.
Meanwhile, Lennie waits at the designated safe spot. He hallucinates about his Aunt Clara and a big scary talking bunny, who insists that Lennie isn’t fit to raise rabbits and that George will soon leave him. Lennie cries out for George, and George appears in the brush. To Lennie’s surprise, George insists he isn’t angry. He says it’s the one thing he wants Lennie to know.
Then, at Lennie’s request, George begins to recount the dream farm story. As George listens to the lynch mob approaching, he instructs Lennie to look away over the river and envision the farm. As Lennie is visualizing the realization of their dream, George shoots Lennie in the back of the head. Lennie goes out without much twitching.
George tosses the gun away and is immediately accosted by the wandering group of vigilantes. He says that, yes, Lennie did have Carlson’s gun until he wrestled it away from him. Slim immediately picks up on what happened here, and tries to assure George that he did the honorable thing. As the two men leave, Carlson and Curley are left behind, completely puzzled at why George and Slim seem so bothered.