Fugitive bank robbers Seth and Richie Gecko hold up a liquor store, killing clerk Pete Bottoms and Texas Ranger Earl McGraw, and in the process, they inadvertently destroy the building. At the motel room where they are hiding out, Seth returns to find Richie has raped and murdered a bank clerk they had taken hostage.
Jacob Fuller, a pastor experiencing a crisis of faith, is on vacation with his teenage children Scott and Kate in their RV. They stop at the motel and are kidnapped by the Geckos, who force the Fullers to smuggle them over the Mexican border. In Mexico, they arrive at the Titty Twister, a strip club in the desert, where the Geckos will be met by their contact, Carlos, at dawn. Carlos will escort them to sanctuary at "El Rey", a place of safety for fugitives from justice whose admission fee is 30 percent of everything they have. When Richie complains to Seth that this too high, Seth tells him it is non-negotiable.
The bar employees reveal themselves as vampires and kill most of the patrons. Richie is bitten by a stripper and dies; only Seth, Jacob, Kate, Scott, a biker named Sex Machine, and Frost, a Vietnam veteran, survive. The others are reborn as vampires, including Richie, forcing the survivors to kill them all. When an army of vampires, in bat form, assembles outside, the survivors lock themselves in, but Sex Machine is bitten, becomes a vampire, and bites Frost and Jacob. Frost throws Sex Machine through the door, allowing the vampires to enter while Frost turns into a vampire.
Seth, Kate and Scott escape to a storeroom, followed shortly by an injured but still alive Jacob, brandishing a shotgun. In the storeroom, they fashion weapons from truck cargo the vampires have looted from past victims, including a stake mounted on a pneumatic drill, a crossbow, and holy water, which requires Jacob to recover his faith to bless. Jacob, knowing he will soon become a vampire, makes Scott and Kate promise to kill him when he changes.
The group make their final assault on the undead. Sex Machine mutates into a large rat-like creature and attacks Seth, but is killed. Jacob becomes a vampire, but Scott hesitates to kill him, allowing Jacob to bite him. Scott hits Jacob with holy water and shoots him. Scott is overwhelmed by vampires, who begin to devour him; he begs for death, and Kate shoots him. As vampires surround Kate and Seth, streams of morning light enter through bullet holes in the building, making the vampires back away. Carlos arrives and his bodyguards blast the door open, letting in the sunlight and killing the vampires.
Seth chastises Carlos for his poor choice of meeting place and negotiates a smaller tribute for his admission to El Rey. Kate asks Seth if she can go with him to El Rey, but he refuses, apparently as a kindness, leaving her with some cash. Kate drives away in the RV, leaving the Titty Twister — revealed to be the top of a partially buried Aztec temple — behind.
