George Milton and Lennie Small are two wandering farm workers who, in their quest for a better life, flee from a pursuing posse and hop onto a freight train destined for the San Joaquin Valley. Their journey leads them to spend the night in a thicket by the Salinas River where George dreams of owning a small farm one day. Unfortunately, this dream is constantly threatened by Lennie, a gentle giant with a simple mind, whose previous actions have brought the posse down upon them. Before they leave their temporary camp, George advises Lennie that if he ever finds himself in serious trouble, he should return to the riverside.
Upon reaching the Jackson ranch, the two manage to secure employment. However, trouble looms when Lennie unintentionally earns the ire of Curley, Jackson's bullying son, who has a strong dislike for larger men. Amidst this tension, they encounter Candy, an elderly swamper at the ranch. Candy befriends the newcomers and warns them about avoiding Curley’s jealous wife, Mae. Later, as George shares his dream of owning a farm with Candy, his new friend offers to invest his life savings into their hopeful venture.
Just as their dreams start to seem within reach, Curley's jealousy gets the better of him. In a fit of rage over his wife's perceived infidelities, he violently confronts Lennie. Initially filled with fear, Lennie's survival instincts kick in, resulting in him crushing Curley’s hand with his immense strength. The escalating situation takes another turn when Mae unexpectedly finds Lennie, George, and Curley in the quarters of Crooks, a crippled African American stable boy. Realizing that it was Lennie who harmed her husband, Mae taunts Curley, further feeding his wrath.
The next day, tensions flare again when Mae attempts to take a puppy given to her by ranch hand Slim. While in the barn, she stumbles upon Lennie, who is mourning the accidental death of his puppy due to his overwhelming strength. In a moment of misguided comfort, Mae invites Lennie to touch her hair. But when she urges him to stop, panic ensues, leading Lennie to unintentionally kill her in a desperate attempt to quiet her screams.
Frightened and confused, Lennie recalls George’s earlier words and flees to the thicket by the river. Meanwhile, Curley forms a posse to hunt down Lennie. In a heartbreaking turn of events, George, determined to protect his friend from a mob’s wrath, takes a pistol, reaches the river first, and finds Lennie waiting anxiously. He tenderly instructs Lennie to focus on their dream of the farm as he describes it in vivid detail. With Lennie’s excitement growing, George makes the devastating decision to end Lennie’s life to spare him from the inevitable brutality of the mob, tragically pulling the trigger as Lennie listens with hope.
