This action-oriented thriller set against the desolate, expansive countryside of West Texas in June, as Ed Tom Bell (Tommy Lee Jones) laments the increasing violence in a region where he, like his father and grandfather before him, has risen to the office of sheriff.
Llewelyn Moss (Josh Brolin), hunting pronghorn in the desert, comes across the aftermath of a drug deal gone awry: several dead men and dogs, a wounded Mexican begging for water, and two million dollars in a leather pilot's case that he takes to his trailer home. After dark he returns with water for the dying Mexican but is chased away by two men in a truck and forced to abandon his vehicle in order to escape.
Returning home he retrieves the money, sends his wife Carla Jean (Kelly Macdonald) to be with her mother, and makes his way to a motel in the next county, where he hides the case in the air duct of his room.
Anton Chigurh (Javier Bardem) is a ruthless hitman who has been hired to recover the money. He has already strangled a sheriff's deputy to escape custody and stolen a car by using a captive bolt pistol to kill the driver. He tracks Moss to his hotel with the aid of a transponder hidden inside the case. Chigurh makes entry into Moss' hotel room, ruthlessly slaughtering the Mexicans preparing to ambush Moss.
However, Moss had previously rented an adjoining hotel room and retrieved the money from the air vent. He escapes undetected. In a border town hotel, Moss finds the electronic bug, but not before Chigurh is upon him. A firefight between them spills onto the streets, leaving both men wounded. Moss flees into Mexico, collapsing from his injuries before he is helped to a local hospital. There, Carson Wells (Woody Harrelson), another hired operative, is unable to persuade him to accept protection in return for the money.
After Chigurh cleans and stitches his own wounds with stolen supplies, he ambushes Wells back at his hotel and kills him, just as Moss telephones the room. Picking up the call and casually raising his feet to avoid the spreading blood, Chigurh promises Moss that Carla Jean will go untouched if he gives up the money. Moss remains defiant.
Moss arranges to meet his wife at a motel in El Paso to give her the money and send her out of harm's way; instead, she reluctantly accepts protection for her husband from Bell. However, Carla Jean's mother unwittingly reveals Moss' location to a group of Mexicans. The sheriff reaches the rendezvous in time to see the end of a gunfight that leaves Moss dead and a Mexican hitman wounded.
That night, Bell returns to the crime scene, nearly encountering Chigurh, who has hidden himself in the closet. Bell notes that the vent cover in the room has been removed, and leaves the scene without further investigation.
Bell visits his Uncle Ellis (Barry Corbin), an ex-lawman. Bell plans to retire because he feels "overmatched," but Ellis points out that the region has always been violent. For Ellis, thinking it is "all waiting on you, that's vanity."
Carla Jean returns from her mother's funeral to find Chigurh waiting in her bedroom.
When she tells him she does not have the money, he recalls the pledge he made to her husband that could have spared her. She rebuffs his offer of a coin toss for her life, stating that the choice is his. Chigurh leaves the house, alone, and carefully checks the soles of his boots. As he drives through town, he is injured in a car accident and limps away from his damaged vehicle.
Now retired, Bell shares two dreams with his wife (Tess Harper), both involving his deceased father. In the first, he lost "some money" that his father had given him. In the other, he and his father were riding horses through a snowy mountain pass; his father, who was carrying fire in a horn, quietly rode by with his head down, "going on ahead, and fixin' to make a fire" in the surrounding dark and cold. Bell knew that when he got there his father would be waiting. Then he woke up.