In 1980, hitman Anton Chigurh is arrested in Texas. In custody, he strangles a deputy sheriff and uses a penetrating, air-powered captive bolt pistol to kill a stranger on the highway and escape in his car. He spares the life of a gas station owner who correctly guesses the result of Chigurh's coin toss.

Meanwhile, Llewelyn Moss is hunting pronghorns in the desert. He inadvertently comes across the aftermath of a drug deal gone bad, finding several dead men and dogs, a wounded Mexican man begging for water, drugs in the vehicle, and two million dollars in a briefcase. He takes the money and returns home. Feeling guilty, Moss returns with water that night but finds the man dead. Two men in a truck with a pit bull pursue him, but he escapes into a river. Reaching home, he sends his wife, Carla Jean, to stay with her mother, then takes a taxi to a motel in Del Rio, where he hides the briefcase in his room's air duct.

Chigurh, hired to recover the money, arrives to search Moss' home, where he uses his bolt pistol to blow the lock out of the door. Investigating the break-in, Terrell County Sheriff Ed Tom Bell observes the blown-out lock. Following a tracking device hidden in the money, Chigurh goes to Moss' motel room and kills a group of Mexicans waiting to ambush Moss. Moss has rented a second room adjacent to the Mexicans' room with access to the duct where the money is hidden. He retrieves the briefcase before Chigurh opens the duct.

Moving to a hotel in the border town of Eagle Pass, Moss discovers the tracking device, but Chigurh has already found him. Their firefight spills onto the streets, killing a bystander and wounding both. Moss flees across to Mexico, stashing the case of money along the Rio Grande. Finding Moss severely injured, a passing norteño band takes him to a hospital. Carson Wells, another hired operative, fails to persuade Moss to accept protection in return for the money. Chigurh cleans and stitches his own wounds with stolen supplies and ambushes Wells at his hotel. Unsuccessfully bartering for his life, Wells is murdered by Chigurh. Moss telephones the room, intending to bargain with Wells, but Chigurh answers the call instead and vows to kill Carla Jean unless Moss gives up the money.

Moss retrieves the case from the Rio Grande and arranges to meet Carla Jean at a motel in El Paso, where he plans to give her the money and hide her from danger. Carla Jean is approached by Sheriff Bell, who promises to protect Moss. Carla Jean's mother unknowingly reveals Moss' location to a group of Mexicans tailing them. Bell reaches the motel rendezvous at El Paso, only to hear gunshots and spot a pickup truck speeding from the motel. Bell finds Moss dead in his motel room. Carla Jean arrives later and understands from Bell's expression that Moss is dead.

That night, Bell returns to the crime scene and observes the lock blown out. Chigurh appears to hide behind the door of the room, but when Bell hesitantly enters, he finds the room empty. He sees the vent cover removed. Later, Bell visits his uncle Ellis, an ex-lawman, and tells him he plans to retire because he feels "overmatched" by the recent violence. Ellis tells Bell of a story in which a lawman, Bell's great uncle, was killed on his own porch, and says that the region has always been violent.

Weeks later, Carla Jean returns from her mother's funeral to find Chigurh waiting in her bedroom. She refuses his offer of a coin toss for her life, stating that he cannot pass blame to luck: the choice is his. Chigurh checks his boots as he leaves the house. As he drives through the neighborhood, he is injured in a car crash at an intersection, but survives. He then bribes two young witnesses for a clean shirt and their silence and flees.

Now retired, Bell shares two dreams with his wife. In the first, he lost some money his father had given him. In the other, he and his father were riding through a snowy mountain pass; his father had gone ahead to make a fire in the darkness and wait for Bell.