In 1913 Mexico, Ambrose Bierce wakes from a nightmare where he is killed by Pancho Villa. He then speaks with a local bartender about joining Villa’s revolutionary army, and soon he signs up for a journey toward danger. A stagecoach bound for Mexican soil carries a newlywed pair, Mary Newlie and John Newlie, who intend to travel there to preach Christianity.
Meanwhile, outlaw Johnny Madrid escapes the gallows and abducts his hangman Mauricio’s 19-year-old daughter Esmeralda. Madrid finds an ally in the ambitious young Reece, who hopes to become Madrid’s apprentice as an outlaw. Madrid assembles his gang, with Mauricio and a pursuing posse on their trail, as they move through the arid landscape toward their next confrontation. They later ambush Bierce’s stagecoach, driven by Reece’s belief that Bierce possesses something of immense value. Yet they find nothing of material worth; Bierce insists that he is, in fact, the invaluable object, intending to join Villa’s cause. Madrid, irritated, abandons Reece, leaving her to be tracked by the posse.
As night falls, every party seeks shelter at La Tetilla Del Diablo, a remote inn that also doubles as a brothel. There they encounter Ezra Traylor, a businessman en route to the United States. Mauricio suspects the establishment is run by vampires, led by high priestess Quixtla, who is immediately drawn to Esmeralda.
When darkness deepens, John clashes with one of Madrid’s men, drawing blood. The vampires reveal themselves, seal the exits, and attack: they kill most of Mauricio’s men and the remnants of Madrid’s gang, sparing only Joaquin and Madrid. Vampire women feed on Ezra, turning him into a vampire, and he hypnotizes and bites Mary Newlie. Madrid, Bierce, Reece, John, Esmeralda, Mauricio, and Joaquin flee into the dungeon beneath the inn and must work together to escape.
Mary rises as a vampire and pursues the group, exposing that John is a fraud who married Mary for her family’s money. John kills Mary in a desperate act. Joaquin, who carries a bite from a previous encounter, turns and bites John; John then persuades Madrid to stake him to prevent his turning. Bierce reveals that Reece is an outlaw who killed her own family, and the surviving group returns to the bar entrance only to find Quixtla and the vampires waiting. Quixtla explains that Esmeralda is the dhampir daughter of Quixtla and Mauricio and will become a full-fledged vampire princess, Santánico Pandemonium. Mauricio had attempted to raise Esmeralda as a human, but his mistreatment and Madrid’s kidnapping brought her back to Quixtla.
Madrid, Mauricio, Bierce, and Reece are hung upside-down to be fed on later as Santánico Pandemonium’s lineage is revealed and Esmeralda’s transformation begins. Madrid breaks free and frees the others. Reece is bitten in the ensuing struggle while Madrid slays Ezra. Santánico strikes down her grandmother and then bites and turns her father into a vampire; yet the elder’s act of opening the entrance and exposing Quixtla to sunlight interrupts the change, allowing Madrid and Bierce to escape while Santánico hides. Santánico calls out to Madrid not to leave as the entrance seals behind them. Madrid looks on with sorrow and chooses to join Ambrose Bierce on his quest to reach Villa’s army, departing together as they overlook a hidden Mayan temple behind the vampires’ lair.
Back in the present, Bierce continues his tale to a patron, claiming to have proof. He reveals a shocking twist: Quixtla herself bit him as they fell outside the bar, and Bierce is now a vampire. The story ends with a brutal flourish as he rips out the patron’s heart and bites it, leaving the audience with a lingering sense of unease about what he has proven and what remains secret.
