Blood Meridian tells the story of a lone "Kid", born into a lawless 1830s America and destined to experience some of the worst violence of the era in Mexico.

From his native Tennessee, he moves through street fights and stabbings to Nacogdoches, Texas, where he meets two special individuals: Judge Holden is a hairless mystery who everyone seems to have some connection to; Toadvine is a criminal reprobate whose ears have been cut off.

The Kid establishes a reputation as a fighter and is recuited by Captain White to join a band of filibusters heading to Mexico in search of war and glory. Their mission is brought to a violent and premature end by Comanche warriors. The Kid survives, but is arrested by the Mexican authorities and taken to the town of Chihuahua where he finds Toadvine in jail.

John Joel Glanton, a true life mercenary, rescues the Kid and Toadvine by recruiting them to his band of scalphunters. Glanton has been awarded contracts by the Mexicans to kill Apaches along the U.S.-Mexican border. Glanton's confidante is the enigmatic Judge Holden.  The scalphunters are glorious in their pursuit of Apaches, killing men, women and children in large numbers. But then, driven by bloodlust and arrogance, they extend their slaughter to Mexican villagers, Mexican soldiers, and anyone else who crosses their path.  They drink and whore their way around the border region, accumulating treasure and leaving towns wrecked and bodies scattered everywhere.

Eventually the gang arrive at the great Colorado River at Yuma, Arizona, where they seize control of the vital ferry boat and extort fortunes from those needing to cross. Their ruinous reign over the crossing is brought to an end when the Yuma Indians attack, killing Glanton and most of the gang.  The Kid and a few survivors escape into the desert, where they turn against each other.   The Kid makes it out alive and heads to Los Angeles, where he becomes the last member of the gang alive... except for the Judge.

Many years later the Kid, now "the Man", travels to Fort Griffin, Texas.  Who should be waiting for him there but Judge Holden, looking the same as ever. In their final, climactic encounter, the apparently ageless and otherworldly Judge kills the Man.  As the book closes, he is dancing and playing the fiddle among the drunkards and the whores of a saloon, claiming that he will never die...