Blood Meridian begins with the introduction of the kid, a 14-year old boy from Tennessee who was born during a meteor shower and has a violent streak.
After the deaths of his parents, the kid runs away to Memphis and eventually ends up in Nacogdoches, Texas, which is where he first encounters Judge Holden, a large, charismatic, and eloquent man. The kid gets into a bloody fight with an outlaw named Toadvine, but they eventually team up to torch a hotel.
After that, the kid rides out of Nacogdoches and spends the night in a hermit's shelter. The next day, he sets his sights on Bexar (current-day San Antonio). The kid tries to barter his labor for a drink at the local bar, and when the bartender refuses, he breaks a bottle over the bartender's head and kills him. He steals a bottle of whiskey, gathers his mule, and moves on out of town. While the kid is resting under a tree, a man named Sergeant Trammel recruits him to join Captain White's company. The Americans have hired White to kill Mexicans. The kid agrees, but soon after joining White's gang, a large portion of the company is massacred during a battle against the Comanches; the kid is one of only eight survivors. He and a man named Sproule trudge through the Mexican countryside in search of water. After Sproule dies, the kid is captured by Mexican soldiers. While they are bringing him to a prison in Chihuahua, the kid sees Captain White's decapitated head being paraded around in a bottle.
The kid is reunited with Toadvine in prison. The outlaw engineers both his and the kid's release by signing them up to join John Joel Glanton's scalp-hunting gang, of which Judge Holden also happens to be a member. From this point onwards, the novel has an episodic structure as John Joel Glanton's company travels through Mexico. The kid witnesses a few isolated scalpings almost immediately. The company then encounters a group of Americans who were heading towards California to prospect for gold, but have been sidetracked by Apache attacks en route.
Judge Holden makes a habit of giving impromptu lessons on geology, nature, and philosophy to anyone who will listen, and he frequently walks around in the nude. Tobin, an ex-priest, becomes friendly with the kid. He tells the kid that Glanton's company first came upon the Judge sitting alone on a rock. He subsequently helped them to formulate their own gunpowder using natural ingredients. Since then, the Judge and Glanton have travelled side by side. Tobin isn't sure if the Judge is just a bit unorthodox or completely insane, but every man in the company has his own outlandish story about encounters with the Judge even before he joined up with Glanton.
Winter settles in. As Glanton's gang moves forward, they pass the ruins of many ancient civilizations, like the Anasazi, who were decimated by American and Mexican soldiers. The Judge describes war as God and believes that human beings' cycle of violence will never end. One day, the company comes upon a camp of Gileno Indians, all of whom are sleeping peacefully. Glanton descends upon them and his men follow suit - the gang members kill every man, woman, and child they can get their hands on. Afterwards, Glanton explains that he thought that Gomez, the man whose scalp carries the highest reward, had been residing in this camp, but he was mistaken. Needless to say, the resulting brutalities are severe.
In July of 1849, Glanton and his gang arrive back in Chihuahua to a hero's welcome. The scalps they have collected are displayed in the main square. Every man gets a sack of gold and they spend their newfound wealth on getting outrageously drunk before setting off again. Glanton's gang quickly develops a reputation throughout the region; when they arrive in new towns, people scurry away in fear. It's not just Indians who are at risk; Glanton's gang has a habit of scalping Mexicans and even a few Americans.
In December, they enter Sonora and get a new contract to furnish more Apache scalps. They set out again. Their first conflict is with a group of Mexican soldiers, whom they kill. They ride on through Santa Cruz and end up in Tucson. There, they pick up a man known as the owner, who brings his mentally disabled brother along. The company refers to the latter man as the Idiot.
The company arrives at the Colorado River, where a ferry run by Dr. Lincoln takes passengers across. They refuse to pay. Instead, Glanton makes a deal with some nearby Yuma Indians to take over the ferry and run it themselves. However, Glanton double-crosses the Yumas and massacres several of them instead. The surviving Yumas attempt to run another ferry downriver, but Glanton kills their operator. Ultimately, the Yumas take revenge on Glanton and his gang, attacking their encampment while most of the men are sleeping off their drunkenness. Most of the company perishes in this attack, including Glanton. Toadvine, Tobin, the kid, David Brown, Judge Holden, and the Idiot survive. Tobin and the kid, both of whom are nursing severe injuries, run away from the Judge and flee all the way to San Diego. There, Tobin seeks medical help, and the kid has surgery. They never re-unite. Years later, the kid sees Toadvine and Brown getting hanged in Los Angeles.
Once he is an adult, the kid (now referred to as the man) lives a more honest life. One day, he runs into Judge Holden at a dancehall. The Judge is bald, tall, and effusive as ever, and he tells the man that he is disappointed in him and once again praises the godly act of war. It is suggested that the Judge waits for the man to go to the latrine and kills him while he sits on the toilet, but the events are not entirely clear. Nevertheless, the Judge re-enters the dancehall and plays the fiddle for all the drunkards and whores, chanting that he will never die.
There is a mysterious epilogue about an unnamed man digging holes in the desert and lighting fires in them, all as wanderers follow him closely.