This action-oriented Western delves into the story of Mattie Ross, whose father was murdered by one of his hired hands, Tom Chaney, when she was 14 years old. While collecting her father's body in Fort Smith, Arkansas, Mattie queries the local sheriff about the search for Chaney.
After being told that Chaney has fled with "Lucky" Ned Pepper and his gang into Indian Territory, where the sheriff has no authority, she inquires about hiring a Deputy U.S. Marshal. The sheriff gives three recommendations, and Mattie chooses to hire Rooster Cogburn, whom the sheriff had described as being the "meanest". The taciturn, one-eyed Cogburn rebuffs her offer, not believing she has the reward money to hire him. She raises the money by aggressively horse-trading with Colonel Stonehill, who did business with her father.
Meanwhile, Texas Ranger LaBoeuf arrives in town on the trail of Chaney for the murder of a Texas State Senator. LaBoeuf proposes to team up with Cogburn, who knows the Choctaw terrain where Chaney is hiding, but Mattie refuses his offer. She wishes Chaney to be hanged in Arkansas for her father's murder, not in Texas for killing the senator.
Mattie also insists on traveling with Cogburn to search for Chaney and secure her $50 payment, but Cogburn later leaves without her, having gone with LaBoeuf to apprehend Chaney.
After being refused passage on the river ferry that conveyed Cogburn and LaBoeuf, Mattie crosses herself on horseback. LaBoeuf expresses his displeasure by birching Mattie with a stick, but Cogburn eventually stops him. After a dispute over their respective service with the Confederate States of America, Cogburn ends their arrangement and LaBoeuf leaves.
Later, while pursuing the Pepper gang that Chaney is reportedly traveling with, the two meet a trail doctor who directs them to an empty dugout for shelter. There they find two outlaws, Quincey and Moon, and interrogate them. Soon Moon, fearful of losing his leg, acquiesces by divulging what he knows to Cogburn, Quincey then fatally stabs Moon, and Cogburn shoots Quincey dead. Before dying, Moon says Pepper and his gang will be returning later that night.
Just before they arrive, LaBoeuf arrives at the dugout and is confronted. Cogburn, hiding on the hillside with Mattie, shoots two gang members and LaBouef, but Pepper escapes. The next day, Cogburn gets in a drunken argument with the wounded LaBoeuf, who departs once again. While getting water from a nearby stream, Mattie encounters Chaney. She shoots and wounds him, but he survives and drags her back to Ned, who forces Cogburn to leave by threatening to kill her.
Being short a horse, Ned leaves Mattie with Chaney, ordering him not to harm her or he will not get paid after his remount arrives. Once alone, Chaney disobeys Ned and tries to knife Mattie. LaBoeuf suddenly appears and knocks Chaney out, explaining that he rode back when he heard the shots, and he and Cogburn devised a plan.
They watch from a cliff as Cogburn takes on the remaining members of Ned's gang, killing two and wounding Ned, before his horse is shot and falls, trapping Cogburn's leg. Before Pepper can kill him, LaBoeuf snipes Pepper from roughly four hundred yards away with his Sharps Rifle. Chaney however regains consciousness and knocks LeBoeuf unconscious with a rock.
Mattie seizes LaBoeuf's rifle and shoots Chaney in the chest. The recoil also knocks her into a deep pit. Cogburn soon arrives, but Mattie is bitten by a rattlesnake before he can get to her. Cogburn cuts into her hand to suck out as much of the venom as he can, and then rides day and night to get Mattie to a doctor, carrying her on foot after Blackie her horse collapses from exhaustion, finally making his way to Bagby's store.
Twenty-five years later, in 1903, Mattie reveals through narration that her left forearm was amputated due to gangrene from the snakebite. Cogburn stayed with her until she was out of danger, but left the store before she regained consciousness. She never saw Cogburn again, despite a letter she wrote to him inviting him to visit and to collect the extra $50 she still owed him.
She receives a note from Cogburn inviting her to meet him at a travelling Wild West show in which he now performs. She arrives, only to learn that Cogburn died three days earlier. She has his body moved to her family cemetery. Standing over Cogburn's grave, she reflects on her decision to move his remains, and about never having married. She also reveals that she never saw LaBoeuf again, though she would like to, and observes that "time just gets away from us".