This article's plot summary may be too long or excessively detailed. Please help improve it by removing unnecessary details and making it more concise. (March 2016) (Learn how and when to remove this template message)
In rural Texas, go-go dancer Cherry Darling (Rose McGowan) decides to quit her low-paying job and find another occupation. She runs into her mysterious ex-boyfriend El Wray (Freddy Rodriguez) at the Bone Shack, a BBQ restaurant owned by J.T. Hague (Jeff Fahey) and his sheriff brother (Michael Biehn). Meanwhile, a group of officials at a nearby US military base, led by the demented Lt. Muldoon (Bruce Willis), are making a business transaction with a chemical engineer named Abby (Naveen Andrews) for mass quantities of a deadly biochemical agent known as DC2 (codename "Project Terror"). When Muldoon learns that Abby has an extra supply on hand, he attempts to take Abby hostage, and Abby intentionally releases the gas into the air. The gas reaches the town and turns most of its residents into deformed bloodthirsty psychopaths, referred to as "sickos" by the surviving humans. The infected townspeople are treated by the sinister Dr. William Block (Josh Brolin) and his unhappy, unfaithful bisexual anesthesiologist wife Dakota (Marley Shelton) at a local hospital.
Random zombie attacks begin along the highway, causing El Wray, with Cherry as his passenger, to crash his truck. In the aftermath, several zombies tear off Cherry's right leg. Also falling victim, fatally, is Tammy (Stacy "Fergie" Ferguson), who was on her way to into town to reunite with her former lover Dakota. When Tammy's body arrives at the hospital, Dr. Block recognizes her and by comparing text messages on the cellular phones of Tammy and his wife, realizes Dakota was about to leave him. He then attacks Dakota with her own anesthetic syringe needles, stabbing her repeatedly in the hands, rendering them useless, before locking her in a closet to tend to other patients, including Cherry, who is still alive.
El Wray is detained by Sheriff Hague based on past encounters between the two men. As the patients transform into zombies, El Wray leaves the police station and arrives at the hospital, attaching a wooden table leg to Cherry's stump. As El Wray and Cherry fight their way out of the zombie-infested hospital, Dakota escapes to her car, but in struggling to open its door with her numbed hands, accidentally breaks her left wrist. She eventually manages to drive away. Meanwhile, Block becomes infected along with others, while Cherry and El Wray take refuge at the Bone Shack.
Dakota retrieves her son Tony (Rebel Rodriguez) and takes him to her father, Earl McGraw (Michael Parks), a Texas Ranger. Tony, who was given a revolver by his mother, accidentally shoots himself in the face after being told not to point it at himself. Cherry and El Wray make love in J.T.'s bedroom. Due to a "missing reel", what happens immediately following this is not known, but when the film returns, Sheriff Hague has been shot in the neck by one of his own officers, zombies are massing outside the Bone Shack, which is set on fire, and Wray has evidently told Hague who he really is, with both men hinting at some important backstory dialogue that probably happened during the "missing reel". Dakota, Earl, and Tony's crazed babysitter twins (Electra and Elise Avellan) arrive at the Bone Shack. With Sheriff Hague badly injured, the group decides to flee to the Mexican border, before being stopped by a large mob of zombies. Muldoon's men arrive, and kill the zombies before arresting the group. They learn from Abby that the soldiers are stealing Abby's supply of the gas because they are infected with it and the only treatment is by constant inhalation of the gas, which delays mutation. They also learn that a small percentage of population is immune to the gas, suggesting a possible treatment, which is why Muldoon quarantined the survivors.
As Cherry and Dakota are taken away by two soldiers (Quentin Tarantino credited as "Rapist #1" and Greg Kelly credited as "Rapist #2"), the others defeat the security guards. J.T. sustains a gunshot wound in the process, and the group searches for Muldoon. Discovered by El Wray and Abby, Muldoon explains that he killed Osama bin Laden before he and his men were infected with DC2 and were ordered to protect the area. El Wray offers a respectful recognition of Muldoon's military service before he and Abby shoot the mutating Muldoon.
Meanwhile, Cherry is forced to dance by Rapist #1 while being held at gunpoint. Cherry attacks by breaking her wooden leg across the rapist's face and stabbing him in his eye with the stump. Dakota, after realizing she has regained feeling in her hands, quick-draws her syringe launcher and stuns Rapist #2. El Wray and Abby arrive to rescue Cherry and Dakota, and El Wray replaces Cherry's broken wooden leg with a modified M4 Carbine with a M203 grenade launcher attachment. She promptly kills Rapist #1 and several zombies with it.
J.T., wounded and lying beside his dying brother, stays behind to detonate explosives to eliminate the zombies still in the complex while the others flee. The survivors make plans to escape by stealing helicopters but must fight past the remaining zombies. Abby dies (and hope for a cure with him) when a ballistic projectile blows his head up. An infected Block then arrives and is killed by Earl, shortly before the survivors use the blade tips of their transport helicopter to kill all the remaining zombies. However, while saving Cherry from a zombie, El Wray is fatally wounded. In the epilogue, Cherry (now sporting a minigun prosthetic leg) leads the group and many more survivors to the Caribbean beach at Tulum, Mexico, where they start a peaceful new society during a world-wide zombie outbreak. In the final moments of the film, it is revealed that Cherry Darling has given birth to El Wray's daughter (alluded to earlier during El Wray's final scene when he puts his hand on her stomach and restates his motto "I never miss").
In a post-credits scene, Dakota's son Tony is sitting on the beach at the survivor's "base" playing with his turtle, scorpion, and tarantula.
Who replaces Cherry's broken wooden leg?
El Wray