Fugitive bank robbers and brothers Seth (George Clooney) and Richie Gecko (Quentin Tarantino) are fleeing the F.B.I. and Texas police. During the first few minutes of the film, they hold up and then destroy a liquor store and kill the clerk, and a cop. Two witnesses they held hostage in the store can escape during the shooting. They still hold a bank clerk hostage in the trunk of their car, whom Richie later rapes and murders (offscreen).
The Fuller family — Jacob (Harvey Keitel), the father and a pastor who is experiencing a crisis of faith; his son Scott (Ernest Liu); and daughter Kate (Juliette Lewis) — are on a vacation in their RV. They stop at a motel and are promptly kidnapped by the Geckos, who force the Fullers to smuggle them past the Mexican border. Seth and Jacob make an uneasy truce: if the Geckos can make it past the border, Jacob and his family will come out of the ordeal unharmed. They succeed and arrive at the "Titty Twister", a strip club in the middle of a desolate part of Mexico, where the Geckos will be met by their contact Carlos (Cheech Marin) at dawn. The Geckos demand that the Fullers have a drink with them before leaving, despite Kate's obvious discomfort.
Bikini-clad Salma Hayek, as Santanico Pandemonium, performs an erotic dance with a snake.
Soon after entering the club, chaos ensues as the employees and strippers are all revealed to be vampires. Most of the patrons are quickly killed, and Richie is bitten by the star stripper, Santanico Pandemonium (Salma Hayek), and bleeds to death. Only Seth, Jacob, Kate, Scott, a biker named Sex Machine (Tom Savini) and Frost (Fred Williamson), a Vietnam War veteran, survive the attack. The slain patrons — including Richie — then come back to life as vampires, forcing Seth to kill his own brother.