The novel follows an adolescent runaway from home with a disposition for violence, known only as "the kid," who was born in Tennessee during the famous Leonids meteor shower of 1833. In the late 1840s, he first meets an enormous and completely hairless character, Judge Holden, at a religious revival in Nacogdoches, Texas. There, Holden shows his dark nature by falsely accusing a preacher of raping both a young girl and a goat, inciting those attending the revival to physically attack the preacher.
The kid carries on journeying alone on his mule through the plains of eastern Texas, and he spends a night in the shelter of a recluse before arriving in "Bexar" (the county that includes modern-day San Antonio). After a violent encounter with a bartender which establishes the kid as a formidable fighter, he joins a party of ill-armed U.S. Army irregulars, led by a Captain White, on a filibustering mission to claim Mexican land for the United States. Shortly after entering Mexico, they are attacked, and many killed, by a band of Comanche warriors. Arrested in Chihuahua, the kid is set free when his cell neighbor and prior acquaintance, the earless Louis Toadvine, tells the authorities that the two of them would make useful recruits for the state's newly hired scalp hunting operation, led by John Joel Glanton.
Toadvine and the kid consequently join Glanton's gang. The bulk of the novel is devoted to the detailing of the gang's conversations and depraved activities. The gang encounters a traveling carnival, and, in untranslated Spanish, each of their fortunes is told with Tarot cards. The gang originally contracts with various regional leaders to exterminate Apaches and are given a bounty for each scalp they recover. Before long, however, they murder any in their path, including peaceful agrarian Indians, unprotected Mexican villagers, and even Mexican soldiers.
Judge Holden, who re-enters the story as a fellow scalp hunter, is presented as a profoundly mysterious and awe-inspiring figure; the others seem to regard him as not quite human. He is strongly implied to be a child-killer though almost no one in the gang expresses much distress about this. According to an ex-priest gang-member named Ben Tobin, the Glanton gang first met the judge while fleeing from the onslaught of a much larger group of Apaches. In the middle of the desert, the gang found Holden sitting on an enormous boulder, where he seemed to be waiting for them all. He took them to an extinct volcano, and improvised gunpowder from natural materials, enough to give them the advantage against their Apache pursuers. When the kid remembers seeing Holden in Nacogdoches, Tobin explains that each man in the gang claims to have met the judge at some point before joining Glanton's gang—though he ends his tale by stating that he first met with the judge in the desert with the others. This suggests a potentially disingenuous quality to the refrain "the priest doesn't lie" uttered by several characters throughout the course of the novel.
After months of marauding, the gang crosses into U.S. territory, where they set up a systematic and brutal robbery operation at a ferry on the Colorado River near Yuma, Arizona. Local Yuma (Quechan) Indians are approached to help the gang wrest control of the ferry from its original owner, but Glanton's gang betrays the natives, using their presence and previously coordinated attack on the ferry as an excuse to seize the ferry's munitions and slaughter the Yuma. Because of the new operators' brutal ways, a group of U.S. Army soldiers sets up a second ferry at a ford upriver to cross—which the Yuma briefly appropriate until their ferryman is decapitated and thrown in the river. Eventually, after the gang had amassed a fortune by robbing the settlers using the ferry, the Yumas suddenly attack the gang and kill most of them, including Glanton.
The kid, Toadvine, and Tobin are among the few survivors who flee into the desert though the kid takes an arrow in the leg. Heading west together, the kid and Tobin again encounter Judge Holden, who first negotiates, then threatens them for their weaponry and possessions. Holden fires a non-fatal shot to Tobin's neck and Tobin, and the kid hide among bones near a desert creek. The judge delivers a speech advising the kid to reveal himself. Tobin and the kid continue their travels independently, passing each other along the way. Although the kid has several opportunities to shoot the judge, as Tobin advises, he only attempts so once and fails.
Both parties end up in San Diego, but the kid gets separated from Tobin when he is caught by local authorities and imprisoned. Holden visits him in jail, stating that he told the jailers "the truth": that the kid alone was responsible for the end of the Glanton gang. The kid declares that the judge was responsible for the gang's evils, but the judge denies it. After reaching through the cell bars to try to touch the kid, Holden leaves the kid alone, stating that he "has errands." The kid then tells the authorities where the Glanton gang's fortune can be found, and he is released to go seek a doctor to treat his wound. Under the influence of medicinal ether, he hallucinates that the judge is visiting him, along with a curious man who forges coins. The kid recovers and seeks out Tobin, with no luck. He makes his way to Los Angeles, where he witnesses the execution of the last remaining members of the Glanton gang—Toadvine and David Brown—leaving now only Tobin (assuming he is alive), the judge, and the kid.
The kid again wanders across the American West, and decades are compressed into a few pages. In 1878, he makes his way to Fort Griffin, Texas and is now referred to by the author as "the man." The lawless city is a center for processing the remains of the American bison, which have been hunted nearly to extinction. At a saloon, the man yet again meets the judge, who does not seem to have aged in the intervening years. Holden calls the man "the last of the true," and the pair talk on equal terms. Holden describes the man as a disappointment, stating that he held in his heart "clemency for the heathen." Holden declares prophetically that the man has arrived at the saloon for the dance. The man tells the judge, "You aint nothin" and, notes of a trained bear at the saloon that is performing a dance, that "even a dumb animal can dance."
The man hires a prostitute, then afterward goes to an outhouse under another meteor shower. In the outhouse, he is surprised by the judge, naked, who "gathered him in his arms against his immense and terrible flesh." This is the last mention of the man, though in the next scene, two men from the saloon approach the outhouse, open the door, and gaze in awed horror at what they see, stating only, "Good God almighty." The last paragraph finds the judge back in the saloon, dancing in the nude and playing fiddle wildly among the drunkards and whores, claiming that he will never die.
A brief epilogue features an unspecified person auguring a row of holes across the prairie. The worker sparks a fire in each of the holes while an assortment of passionless wanderers crosses the row. The line of holes is described as "a validation of sequence and causality as if each round and perfect hole owed its existence to the one before it there on that prairie."