Texas sheriff Edgar McGraw pulls up to an isolated liquor store in Texas called Benny's World of Liquor. Once inside he speaks with the shopkeeper. He then goes to use the restroom. As soon as he is inside the bathroom, The Gecko Brothers, Seth (George Clooney) and Richie (Quentin Tarantino), two desperado-type crimminals appear with two hostages and gun pointed at the shopkeeper apparently in the store the whole time. Seth threatens the shopkeeper and tells him to be cool. The sheriff returns shortly after and goes to pay. While talking to the shopkeeper, Richie kills the sheriff with a point blank shot to the head. Seth and Richie argue because Richie claims the shopkeeper mouthed "help us". As the shopkeeper yells to defend himself, Richie shoots him in the shoulder. Seth and Richie argue and Seth decides to leave. As they are leaving the shopkeeper jumps up and shoots Richie in his hand. They all start shooting and the gunfight. The hostages escape and the fight is ended when Seth throws a lit toilet paper roll dosed with light fluid at the shopkeeper who was covered in alcohol killing him. They leave as the liquor store explodes.
The brothers then check into a motel with their one remaining hostage and they discuss their plan to flee to Mexico and meet Seth's contact, Carlos (Cheech Marin) for sanctuary.
A news story is shown about the Grecko brothers and they atrocities. Seth returns to the motel to discover that Richie had raped and murdered the hostage. Seth scolds the insane Richie, for now they need new hostages to escape into Mexico.
The brothers then run into Pastor Jake Fuller (Harvey Keitel), his two kids his teenage daughter Kate (Juliette Lewis) and adopted teenage son Scott (Ernest Liu). They kidnap the family and hijack their R.V. forcing them to drive to Mexico. The group is stopped at the border and the R.V. is searched by a custom's agent (Cheech Marin) but the brothers are hiding in the bathroom with Kate. They eventually make it through and on into Mexico.
Soon after they enter Mexico, they arrive at an eccentric bar called The Titty Twister in the middle of a vast desert. Seth gets into a fight with the head bouncer (Cheech Marin) outside the club who refuses to let them in, and they all go inside. Once inside, they have a few drinks and enjoy the girls dancing on the tables. Soon Santanico Pandemonium (Salma Hayek) performs. Towards the end of her act, the bouncer returns and tells the bartender and the other what happened. When they confront the group, the crazy Richie pulls out a gun and one of the bartenders stabs his already shot hand to the table and another gunfight ensues.
The brothers come out on top again and Seth goes to look at Richies badly wounded hand as Santanico sees the puddle of blood on the table. She then transforms into a hideous beast-like vampire and attacks Richie, biting him on the neck. Seth shoots Santanico off of Richie, but Richie dies soon after. Not long after the bouncer and the bartenders rise from the dead in the same beast-like vampire state and them and all the dancers... who are also vampires, lock the door and begin brutally feeding on the bar patrons. Seth, the family and a couple of bar patrons fight back manage to kill almost all the vampires.
Seth goes to find his brother's body as the remaining bar patrons realizes the vampire band is still there. As the group goes to attack, they disappear. Seth says his final farewells to Richie but before he can finish, Richie turns into a vampire as well and attacks Seth who manages to get away. They share a moment looking at each other and Seth then decides he must kill Richie and he does.
Seth begins to drink heavily as the remaining group starts to hear a swarm of bats surrounding the bar. The group then realizes that the killed bar patrons are turning into vampires as well and must fight them off. While staking the remaining vampires, one of the surviving bar patrons named Sex Machine (Tom Savini) bites his arm but hides it from the others.
The survivors regroup and plan on what to do next. It is not long before Sex Machine begins to transform. He then sneaks up and attacks the other surviving bar patron, Frost (Fred Williamson) biting him in the neck. Sex Machine then moves onto Jake, biting him in the arm. Frost, still in human form, confronts Sex Machine and they begin to fight ending when Frost throws Sex Machine through a window, opening the way for the swam of vampire bats to come in and Frost also transforms. Seth and the kids then run and hide in a back room of the bar.
Jake bandages his arm and makes a cross out of a bat and a shotgun and makes his way back to the remaining group. They then prepare to make a last stand against the remaining vampires. Before they go into battle, Jacob forces his children to swear they will kill him when he turns into a vampire and the reluctantly do.
During the battle, Seth confronts Sex Machine for the final time and is almost killed but he is saved at the last minutes but Kate. The vampire Frost then confronts Jake and Jake kills him with his cross shotgun. Right after he kills Frost, he then too turns into a vampire and attacks his son Scott, biting him in the neck. Scott then kills his father with holy water, and is swarmed by vampires who tear him apart. He then begs his sister Kate to kill him and eventually she shoots him which results in small blast killing the vampires around him.
Now only Seth and Kate remain to fight off the vampires. They are completely outnumbered and it seems all is lost when rays of sunlight start to come through cracks hurting the vampires. They then hear Carlos banging on the door and eventually he breaks through as Seth and Kate run out. The vampires begin exploding and the bar itself explodes as they are running away.
Outside, Seth and Carlos negotiate a deal for the money and Carlos gives Seth a sports car. Seth tells Kate to go home and he drives off, following Carlos onto El Rey. Then the camera shot zooms out to reveal that the bar is actually the top portion of a very large ancient Aztec ziggurat.