The film is set in a nearby town immediately after the events of the first film. The monsters have made it into a small neighboring town in the middle of nowhere and the locals have to band with the survivors of the bar slaughter to figure out how to survive.
The film opens with brief clips from the previous installment which the survivors Bozo, Hot Wheels, and Tuffy/Heroine 2 driving off in the brown Trans Am into the sunrise. As the movie begins, Biker Queen spots a dog running around with a part of an arm belonging to Harley Mom from the previous film. She promptly shoots the dog several times, and takes the hand, matching it to the tattoo on her own hand, which completes the word "Sister". Upon discovering the surviving Bartender from the previous film, she tortures him into telling her who killed Harley Mom. He reveals that it was Bozo and points her to a town where he lived and would have been hanging out. She knocks Bartender out and takes him with her down the road to the town.
Meanwhile, we are introduced to the town’s inhabitants as it becomes overrun with the monsters. First are a pair of small Mexican wrestlers named Thunder and Lightning. Lightning is having sex with his girlfriend when a monster attacks her and while being pulled through a window she is decapitated. They run away in terror as the monsters ravage the trailer park. A bloody slaughter at the jailhouse shortly follows. A hobo is in a cell for dealing meth. The Sheriff then spits in his face and goes off to find his meth lab. The monsters attack but he is safe in the cell, and able to reach out and get the Sheriff’s keys, before the monsters drag away his body. We are then introduced to a brash auto salesman named Slasher. He is in the midst of talking to someone on the phone about finding evidence of his wife cheating and making a sale to a family. He puts the call on hold to finalize the sale as the family is disgusted with his conversation. He is spooked by an attack from one of the monsters and escapes in his car. After hitting some people and a monster he discovers his wife Secrets having sex in the back of the car with a redneck named Greg.
The following morning, Biker Queen and four of her biker friends arrive in the deserted town, seemingly ignoring the dead bodies and decapitated heads in the streets as they look for Bozo. They cross paths with Slasher, Secrets and Greg who are in hiding. One of the biker girls is almost killed as a car falls out of the sky with a monster in it. It jumps out of the car and chases them to Slasher's office. The monster brutally kills a biker girl as she is left behind. The wall of their shelter collapses and the group escapes into the neighborhood. The biker girls and the Bartender make their way to Bozo's apartment where they encounter a family across the hall who want them to leave. The bikers slaughter the family and a girl in a back room comes out saying she's not armed. The Bartender recognizes her as Honey Pie, the girl who left them at the bar. He brutally attacks her and bites off her ear until she draws a gun. Biker Queen recognizes the gun as Harley Mom’s. She attempts to take the gun but the Bartender knocks Honey Pie out of the window and onto the street.
Slasher, Greg, and Secrets receive a call from the wrestlers but before they find them, they are ambushed by the bikers. Both groups get to the garage where the brothers and their grandmother are in hiding. As the day wears into night, the group finds out the jailhouse is the safest place in town but the hobo has sealed himself in. They come up with a plan to use the brothers' key making skills to get inside. At this time Honey Pie makes her way to safety by crawling into the vent shaft of a convenience store. She comes across a dead body and realizing how unsafe it is finds that she is trapped inside.
As the brothers fashion the key in their workshop across the way, Greg begins dissecting a monster they’d killed. He ends up inadvertently setting off a spout of foul smelling flatulence and accidentally douses the grandmother with green vomit. He continues to poking organs and showering the women with various bodily excretions all the while remaining dry. He then discovers an eye in the monster's body cavity that lets out an ear-piercing wail, which Biker Queen stops with a shotgun. The screaming soon brings other monsters to the garage. The brothers return with the key but the group must go to the roof to escape the monsters. Still trying to escape the store Honey Pie witnesses a cat outside being raped by one of the monsters.
The family that Slasher had sold the station wagon to had been attacked and the parents killed. The survivors on the roof hear the baby crying trapped in the station wagon. Dawn breaks with Greg trying to be heroic and going to save the baby. The monsters attack and he finds he cannot outrun them so he throws the baby into the air, letting it fall to the ground where it is promptly eaten. A biker girl is injured as the monsters reach the roof. The group fights them off as Greg climbs back up. Secrets means to beat Greg with a shovel but stops as a monster climbs up behind him. Honey Pie is then attacked by the cat/monster hybrid spawned from the raped cat. She kills it and finds out using its claw she can slowly chip away the unbreakable glass door to get out.
Slasher has a plan to get to the jailhouse roof and decides they need a sacrifice. They hurl the injured girl off the roof using the distraction to get Biker Queen's motorcycle. They use it to build a makeshift catapult. The grandmother, who is now little more than a whimpering, whining skeleton, due to the eroding vomit she’d been drenched in, is chosen as the catapults test subject. Bartender assures the brothers their grandmother won’t recover and a quick scene of a man dying in the street who’d also been doused in the vomit convinces Thunder. Lightning is still opposed and a fight between the brothers breaks out. He loses and finally agrees to use their grandmother in the catapult. She lands on the roof but is smashed against the wall. Honey Pie escapes from the store as a monster crashes through the ceiling. Thunder gets onto the catapult but is thrown into the street where he is quickly attacked by the monsters.
The group watches as Thunder is disemboweled. Greg notices that the motorcycle is still running and it backfires sending a pipe up into his head. Slasher observes this with a silent, gleeful grin before anyone else notices. Meanwhile, Lightning crosses the street under the protection of a trashcan. Thunder, missing his legs crawls away while Lightning picks up the key he had dropped. Honey Pie is now walking towards the edge of town to a train crossing. Lightning reaches the jailhouse and as he opens the door, but the hobo throws a stick of dynamite out. Lightning ducks down in the trashcan to protect himself from the explosion. The trashcan launches across the street and the handle of it goes flying. Honey Pie, now across the tracks, is struck by the piece of garbage can shrapnel and falls to the ground presumably dead. The others watch as the monsters begin breaking onto the rooftop. Honey Pie's dead face is shown as the credits roll, and blood pools. Suddenly she gets up, screaming in anguish and annoyance then grabs her gun.