Over the opening credits, Cherry Darling (Rose McGowan) works as a go-go dancer at a club. After crying onstage, she tells her boss Skip (Skip Reissig) that she needs to make a real change in her life and quits her job. While walking home, several military trucks pass her close enough that she throws herself into a bunch of trashcans. She also gets several splinters in her thigh for her trouble.
At the military base a couple of miles away from town, scientist Abby (Naveen Andrews) is threatening his incompetent employee Romey (Julio Oscar Mechoso) for having lost three very valuable 'specimens'; the price of failure is Abby's henchmen cutting off Romey's testicles, which Abby keeps in a jar along with a collection of them from other victims. Lt. Muldoon (Bruce Willis) shows up, wearing a gas mask. He asks Abby where the "shit" is, and Abby says that its all there on the base, prompting a short gunfight. His men are shot to death by Muldoon's troops, and he again asks where the mysterious "shit" is. Muldoon's face starts to boil and Abby says that its all around them. He grabs a pistol and blasts a gas canister open, spreading gas everywhere. Some are unfortunately exposed instantly to the gas, melting into gooey messes. However, Muldoon and his men walk into the green gas and enjoy it while Abby escapes in a vehicle, not noticing one of Muldoon's soldiers is riding on top of the vehicle. The green mist spreads through the air.
Meanwhile, Cherry stops at a rundown barbecue restaurant called 'The Bone Shack'. A young woman named Tammy (Fergie) arrives and asks the owner J.T. (Jeff Fahey) for some water for her car's overheated engine. Cherry goes to the dirty ladies room where she cleans her leg wound and sits down in the restaurant where she is the only customer. After Tammy drives away, Wray (Freddy Rodríguez), a local mechanic, arrives in his truck. J.T., obsessed with having the best barbecue in Texas and winning a local contest tells Wray that he is celebrating is restaurant's 25th anniversary. Wray sits at Cherry's table and the two converse, revealing Wray and Cherry have a history together, and she's wearing his jacket. They briefly talk about their past, and Cherry sardonically states that she is going to become a stand-up comedian. Their flame for each is other is clearly still there, and Cherry catches a lift with Wray.
Dr. William Block (Josh Brolin) and Dr. Dakota Block (Marley Shelton) wake up at 8:00 PM for their late shift at the hospital where they work. Through their window, they can see the eerie green mist. Dakota makes breakfast for her husband and son, Tony (Rebel Rodriguez) and slyly texts her lover to pick up Tony, who will be with the babysitter.
In the hospital where Bill and Dakota work, people with strange symptoms start arriving: the first one, Joe (Nicky Katt), has a bite supposedly half an hour old with an advanced stage of gangrene and bacterial infection. Dr. Felix (Felix Sabates) notes he has seen similar wounds before in Iraq soldiers, due to mustard gas. Joe's temperature is high, and when Block makes Joe open his mouth he is startled that his tongue is infected as well. Block squeezes a boil, making it burst and blood and fluid spurt onto his face. The infection on Joe's arm is spreading, so he calls in Dakota and tells Joe that he's going to amputate his arm. Dakota has three needles and injects Joe with all of them, making him pass out.
On the road, Tammy is listening to a radio broadcast dedicated to the memory of someone named Jungle Julia when her car breaks down near the military base. While trying to hitch a ride she is attacked by the infected people (called "sickos"), who tear her apart and drag her body off the road. Wray and Cherry see them dragging the body, but think that it's just a dead deer. (Wray says that its best to run right through a deer if it's in front of you, because trying to swerve might cause you to crash.) He is immediately startled by a sicko in the road and swerves, losing control of his truck. The truck rolls over until its upside down, and Cherry gets after him for swerving; he replies that it wasn't just a deer in the road. Sickos suddenly grab Cherry and take her to the woods. Wray grabs a rifle and runs after her. By the time Wray catches up with them, the sickos have ripped off Cherry's right leg and have run off with it. Wray shoots the sickos, but they don't die. He puts Cherry in his truck and speeds off to the hospital.
At the hospital, Cherry is barely awake when admitted. While Dr. Block asks Wray what happened, Sheriff Hague (Michael Biehn) arrives with Deputy Carlos (Carlos Gallardo) and Deputy Tolo (Tom Savini). Hague is startled to see Wray due to an unexplained secret in his past and asks why he's carrying a rifle. Hague arrests him as more sick people show up. Block calls Dakota over and shows her Tammy's corpse which also arrives. A doctor calls her a "no-brainer", since she's missing the back of her head and her brain. Dakota gets upset and cries in a room while Block follows her. He knows that Tammy and Dakota used to have a lesbian relationship, and that they were going to run off that night. Block grabs one of Dakota's needles and stabs her hands with it, causing her hands to become numb. Before he can kill her, Block is called away by another doctor, but he first locks Dakota in the room. The other doctor tells him that all the dead bodies have disappeared from the morgue, with a thick trail of blood leading away.
At the police station, Wray is permitted to make one phone call where he has a coded conversation with someone on the other end; Wray asks about something called "DC-2", and asks more coded questions. Earl McGraw (Michael Parks), a local Texas Ranger, talks with Wray over his troubles, and leaves for home to care for his sick wife who's dying from lung cancer. Sheriff Hague keeps asking Wray who he really is when he gets a call from his brother J.T., who complains that there are two people loitering in front of his restaurant who aren't customers. Their conversation reveals that Hague owns the diner and is raising J.T.'s rent due to his brother's refusal to reveal his secret barbecue recipe. J.T. tells Hague not to bother coming over, since the people are coming in, but it turns out the people are sickos, and they presumably attack J.T...
Back with the sheriff, Deputy Tolo arrives angry about some maniac that he arrested at Skip's club that bit off his finger. When the cops go outside to investigate, they see that the sicko has escaped from Tolos' cop car. Carlos finds Tolo's ring on the ground, but no finger. As he gives Tolo his ring back, Carlos is bitten on the arm and attacked by sickos. Before they react, Carlos is gruesomely torn apart and eaten by his attackers. Hague and Tolo shoot the sickos, but more show up. Hague and Tolo fight them off as Wray stays inside the station. Tolo is thrown hard against a car, but lives. More police officers, including an attractive female deputy, show up and blast away the sickos. Wray breaks free from his handcuffs after saving Hague's life, and tells him that he's going to the hospital to get Cherry. Hague tells him that they'll take his car. Hague's car explodes, and so the remaining cops get into the back of Wray's truck and head towards the hospital.
At the home of Earl McGraw, he feeds his virtually catatonic cancer-stricken wife some soup. He looks away for a second, and when he looks back she's turned into a sicko; she attacks him almost instantly.
Back at the hospital, more and more people are coming in with boils and infections. Dr. Felix and Dr. Block are unable to comprehend what's happening. As Dr. Block walks down a hallway, he looks into a room where Joe has turned into a sicko and walks towards him with a surgical saw. Joe cuts Block's glasses, but the saw shuts off when he walks too far away from the outlet, pulling out the plug. Instead, Joe bursts a boil on his face and smears his blood all over Blocks' face, infecting him. Also, Cherry wakes up in a hospital room, and is depressed over her severed leg.
Dakota throws herself out of a window, landing in trash outside of the hospital. She goes to her car, but her hands are still numb. She puts her hand through the handle on her car door and kicks the door open, but loses her balance and falls, breaking her left wrist. Dakota gets into the car and puts her keys in with her mouth, then drives off and runs into a lot of cars. As she leaves, Wray and the cops show up. Wray tries to grab a gun, but is stopped by Hague. Instead, Wray grabs a couple of butterfly-knives out of the truck's glove compartment and runs into the hospital as the cops fight the sickos outside. Tolo accidentally shoots a hospital patient wondering around after mistaking him for a sicko.
Wray enters the hospital and finds total mayhem has taken over; the infected corpses and injured are chasing and attacking both doctors and patients ripping them apart and eating them. With his two butterfly knives, Wray, like a professional fighter, charges into the carnage, brutally stabbing, slashing, slicing and dicing all the sickos in his path. He eventually makes it to Cherry's room where she's hiding under a sheet playing dead. He tells her to come with him as the hospital is now on fire from the mayhem, but she can't walk. Wray tells her to suck it up, and breaks a leg from a table, shoving it onto Cherry's stump. Cherry awkwardly walks with Wray through the hospital as he protects her from the sickos. They make it to his truck and drive off hoping to make it to J.T.'s place.
Meanwhile at Dakota's house, the Crazy Babysitter Twins (Electra Avellan and Elise Avellan) talk on their cell phones with their boyfriends while Dakota's son plays with his pets which include a spider, scorpion, and turtle. Dakota, looking exhausted and dishevelled, comes home, and the babysitter twins get angry at her because her friend didn't show up to take her son on time. Dakota kicks them out of her house and tells her son that they have to leave, but before they do he takes every pet he has with them. While Dakota and her son, Tony, are in their car, the Crazy Babysitter Twins attack them with shovels and smash the windshield. She speeds off, causing one of the twins to land hard on the ground. Dakota drives to Earl McGraw's house, and gives her son a pistol. She tells him that if anyone other than her comes to the car, he must shoot them in the head like in his video games. He asks what if it's dad, and she tells him "especially if it's him." Before she leaves, Dakota tells him to be careful or he'll shoot his own face off. As Dakota walks to the house, she hears a gunshot. She runs to the car to find that her son accidentally shot himself in the head. Her grief is interrupted by Block showing up, having turned into a sicko. He holds her by the hair, but she rips herself away from him, grabs her dead son, and knocks on the front door. Earl, who is revealed to be Dakota's father, lets her in; it is apparent from an axe that he's holding and from blood splattered all over the inside walls, that he has killed his infected wife.
Wray and Cherry meet up with Sheriff Hague at J.T.'s restaurant with other survivors from the town where the Sheriff makes them deputies, and they make their way up a hill to J.T.'s. When they get there, they see J.T. lying down on the floor behind the counter, allegedly with his intestines ripped out. Upon further inspection, though, it turns out J.T. was merely unconscious with some barbecued sausages on his stomach, having killed all the sickos by shooting them in the head. Wray tries the sausage, and says that it is the best he's ever had. J.T. tastes the sauce and agrees. His brother, the sheriff, points out that he's bleeding from the temple and it's probably his own blood that's given the sauce the perfect flavour. Afterward, J.T. shows the group some of his escape vehicles. One of which is a chopper motorcycle, while the other is cut and chopped 1950s convertible automobile. Sheriff Hague continues to ask Wray who is really is, but Wray refuses to answer.
Cherry and Wray discuss their previous relationship in J.T.'s bedroom. We learn that Cherry left Wray because he couldn't commit. Wray has Cherry look in the pocket of his coat (that she took when she left). She finds an engagement ring. They have sex.
What happens after this is unclear to us due to a "missing reel," which causes the film to stop abruptly and melt on screen. The theatre apologizes for the inconvenience.
When we do get back to the movie, some 20 minutes of the story have passed. J.T.'s diner is engulfed in flames, besieged by dozens of sickos. A wounded Sheriff Hague is brought inside after he was accidentally shot in the neck by Tolo. More survivors have showed up at J.T.'s place (the babysitter twins, Cherry's boss Skip, Dakota, Earl, and several other people). Also, Wray has evidently told Hague who he really is, with both men hinting at some important dialogue that we would have heard if not for this "missing reel". Hague gives his pistol to Wray, whom he now calls "El Wray". Tolo is against it, but Hague wants Wray to have all the guns. Wray spins his pistols and becomes the leader of the group. Then Tolo is ripped apart and eaten by the sickos who break into the restaurant. The survivors, Wray, J.T., the wounded Hague, and the remaining survivors go outside and see that they're surrounded by the sickos. They unload all their pistols and rifles into them killing several of sickos, but more and more keep on coming. They retreat back inside the burning building and Wray says that someone needs to retrieve his truck so that they can leave. Cherry volunteers and hobbles out as Wray covers her by firing an assault rifle at the dozens of sickos outside. Cherry drives Wray's truck into the restaurant and Hague gets into the driver's seat. The others pile into the back while Skip gets into J.T.'s roofless convertible along with the babysitter twins and Dakota. Cherry rides the motorcycle, and Earl stays behind to provide cover for their escape. After they break through the sickos, the survivors stop at Dakota's car and pull out a minibike, Tony's Pocket Bike, out of the trunk. Dakota rides on the large motorcycle with Cherry as Wray leads the way on the tiny vehicle. They shoot more sickos on the road while Hague runs them over with the truck. J.T.'s dog unfortunately jumps out of the truck and is run over as well.
Near the military base, they are blocked by a wall of sicko zombies on a bridge, which are killed by a bunch of soldiers coming up from behind. They are Muldoon and his men. Muldoon knows who Wray is, and has his men knock him out. When Wray wakes up, he finds himself locked up with the other survivors in the military base (Abby is there as well). We find out "El Wray" is actually a war veteran. The soldiers take survivors as prisoners. Abby reveals to Wray and the others that he is the scientist and businessman who has sold the virus, DC2, to the soldiers. They are infected, but can use the gas itself to control the symptoms.
Two of the militants (one of them is played by a lecherous Quentin Tarantino) grab Cherry and Dakota. Wray tries to help, but is beaten up. On the elevator ride down, the lecherous soldier stops the elevator and takes off his gas mask. He threatens Cherry with his pistol while his face starts to boil. The other military guy tells him to put his mask back on, and when he does his face becomes normal again.
Back in the cell, J.T. rambles on about the barbecue sauce recipe to distract the guard's attention. El Wray, J.T. and a sax playing prisoner (playing the movie's theme song) overpower the guards, but J.T. is shot. El Wray and Abby break out and find Lt. Muldoon who explains what it is actually happening. Lt. Muldoon and his soldiers were in Afghanistan; they'd accidentally found and killed Osama Bin Laden. But as this was against America's interest, so instead of medals they got gassed with DC2, a chemical weapon designed to wipe out entire cities. He figured that the best way to find a cure was to gas a whole town then take the survivors to extract a cure from them. While he talks he has not been wearing his gas mask, so he swells and blisters and finally is shot and killed by El Wray.
Meanwhile, the rapist soldier tells Cherry to dance on her wooden leg, and takes off his gas mask. While she dances, Cherry hits him in the head with her wooden leg, splintering it to a sharp point which she then stabs him in the eye with. Furious, he drops his pants, and we see his crotch turn to mush melt away. Cherry is horrified and backs away. Dakota, finally getting some feeling back into her hands, shoots a dart-like needle in his other eye. Abby and El Wray arrive and shoot the rapist and his partner. They all go back to fetch the others. Sheriff Hague and J.T. are both near death from their gunshot wounds, so they are left behind, in control of a bomb. El Wray sticks a specially crafted custom-made M4A1 carbine assault rifle/M203 grenade launcher into Cherry's stump. She uses it to open the door to the command centre, shooting a grenade through the rapist, whose condition has worsened severely. She shoots all the men in the command centre with the rifle.
The survivors force their way through the dying soldiers to a couple of helicopters using Cherry's new leg and their own guns. The fatally wounded J.T. and Sheriff Hague volunteer to stay behind and blow up the stash of DC-2 canisters with a remote control detonate that El Wray gives to J.T. After the survivors file out of the building, and engage in a gunfight with the soldiers outside, whom are starting to transform into sickos, J.T. finally tells Hague the secret to his rib recipe (canned tomatoes), then blows up the military base. Storming the helicopters, Abby gets killed and Dakota is attacked by Dr. Block in zombie state. Her father, Earl McGraw, suddenly appears and kills him. During the final battle, Cherry launches herself off the ground with her grenade launcher and blows up a bunch of sickos mid-air. When she lands, she spins around and blasts them away. The survivors make it behind the walls and fight the sickos. One of them shoots a rocket at Cherry, but she dodges it and blows him up. All looks well, and Cherry watches the base burn, but doesn't notice a sicko soldier behind her. Wray and the soldier unload into each other, and Cherry runs to the dying Wray.
Everyone gets into the helicopter and Skip flies it, but not before he cuts through a group of sickos with the helicopter's rotary blades. The Crazy Babysitter Twins laugh with glee over the bloodbath and enjoy taking pot-shots themselves at the sickos on the ground, while one gets into the co-pilot seat and turns on the helicopter's windshield wipers to wash the blood splattered on the front windows
El Wray tells Cherry to go to the ocean, turn her back to the sea, and fight. Cherry pleads with him, asking him not to forget his promise of "two against the world"; he says that the promise is still good, as he has made her pregnant ("I told you, I never miss"). Wray dies, and Cherry grabs onto a lowered rope from the helicopter as it flies away.
Cut to Mexico one year later. Cherry tells us via voice-over that she's found other survivors, and that they took Wray's advice and settled down near the ocean in a remote part of Mexico. On the beach, Skip is enjoying this new lifestyle with the Crazy Babysitter Twins by his side, with several armed survivors, including Dakota, patrolling the area for sickos. A sicko pops out to attack a small child in the crowd of survivors when Cherry blasts him away with her new chain-machine gun attached to her leg. The final shot shows Cherry and her baby daughter, the product from her brief period of sex with El Wray, being happy... two against the world.