McCarthy wrote Blood Meridian while living on the money from his 1981 MacArthur Fellows grant. It is his first novel set in the Southwestern United States, a change from the Appalachian settings of his earlier work. In his essay for the Slate Book Review from 5 October 2012 entitled "Cormac McCarthy Cuts to the Bone", Noah Shannon summarizes the existing library archives of the first drafts of the novel as dating to the mid-1970s. The review includes digital archive images of several of McCarthy's own type-script pages for early versions of the novel.
Describing events of extreme violence, McCarthy's prose is sparse, yet expansive, with an often biblical quality and frequent religious references. McCarthy's writing style involves many unusual or archaic words, no quotation marks for dialogue, and no apostrophes to signal most contractions.
McCarthy conducted considerable research to write the book. Critics have repeatedly demonstrated that even brief and seemingly inconsequential passages of Blood Meridian rely on historical evidence. The Glanton gang segments are based on Samuel Chamberlain's account of the group in his memoir My Confession: The Recollections of a Rogue, which he wrote during the latter part of his life. Chamberlain rode with John Joel Glanton and his company between 1849 and 1850. The novel's antagonist Judge Holden appeared in Chamberlain's account, but his true identity remains a mystery. Chamberlain does not openly appear in the novel. Some critics have suggested that "the kid" is a fictional stand-in for Chamberlain.
Elements of the novel are also widely believed to have been at least partially inspired by the writings of T. R. Fehrenbach, specifically his authoritative and highly original histories of Texas, Mexico, and the Comanche.