On board the Predator ship and immediately after the events of Alien vs. Predator we see the body of Predator (“Scar”) erupt with a Chestburster. The chestburster has taken the characteristics of the predator and quickly grows into a new hybrid called a Predalien. It attacks and kills another Predator onboard the ship. In an attempt to kill the creature another Predator fires his plasma caster and inadvertently damages the ship’s hull, causing it to crash in the forests outside the town of Gunnison, Colorado.
The last surviving Predator from the crash activates a distress signal to its home world, just before it is killed by the Predalien.
A boy and his father who are hunting deer see the crash and go to investigate, but before they can raise the alarm, both are impregnated by Facehuggers that had escaped from the crashed ship.
The distress signal reaches the Predator home world and is answered by a battle scarred Predator ("Wolf"). He views a recording from the Predator’s mask that caused the ship to crash-land. He watches how the Predalien killed crew members, the ship’s crash, and knows Aliens are loose on Earth. He prepares his gear, selects a mask, and departs.
Meanwhile, ex-con Dallas Howard has returned to Gunnison after time served in prison. He is greeted by the town’s sheriff, Eddie Morales. Ricky Howard, Dallas’ brother, is jumped by bullies after delivering a pizza to his love interest Jesse. One of the attackers, Jesse’s boyfriend Dale, takes Ricky’s keys and throws them into the sewer drain, forcing Ricky and his brother Dallas to look for them in the sewers. At this point, the hunting pair give birth to Chestbursters and a few more Facehuggers impregnate several homeless people in the sewers. Ricky catches sight of a Chestbuster and he and Dallas leave rattled after hearing a series of hisses and screeching; they also discover the molted remains of another Chestbuster who has now grown into an Alien. Kelly O’Brien comes home after serving her time in the U.S. Army, to an estranged daughter and waiting husband.
Wolf’s ship arrives mere hours after the distress signal is received. He is tasked with eliminating the Aliens and destroying any evidence of the incident. He salvages equipment from the crashed ship and detonates the vessel to eliminate evidence. Among the salvage is a vial of blue, extremely corrosive liquid used to erase biological traces of Aliens and their victims. The local community searches in earnest for the father/son hunting pair, which Wolf manages to find first. He immediately uses the vial to remove evidence of the hunting pair. An officer comes across him as this happens, fleeing once he is discovered. Wolf kills him, skins him and hangs him from a tree top, which is found the next morning by Sheriff Morales.
Wolf locates the nearest area of possible contamination, the city sewer near the forest. He is ambushed by several aliens, and after a brief fight in which he encounters the Predalien (apparently the dominant Alien of the infestation), the Aliens spread throughout the city through a hole in the sewers (created during the fight when Wolf’s dual plasma casters misfired) leading up into the streets, starting a rampage that eventually leads to the destruction of a nearby power plant, forcing the city into darkness.
After barely escaping with their lives, Ricky, Jesse and Dale manage to meet up with Eddie and Dallas. They head to a sporting shop for weapons, contacting the incoming National Guard; within minutes, however, the entire force is eliminated by aliens. Kelly, having lost her husband and barely escaping an alien , arrives with her daughter Molly. They are forced to flee when Wolf arrives, attempting to destroy as many aliens as he can. Dale is killed when a dead Warrior’s acidic blood burns through his face. Wolf’s plasma casters are damaged in the attack, but he is able to modify one into a makeshift plasma pistol.
Meanwhile, as the small group attempts to escape the town, they make contact with Colonel Stevens, who radios that air evacuation will arrive at the town’s center within half an hour. Kelly is unconvinced that there will be a rescue, as the town’s center is a prime position to keep the infestation focused on the survivors, allowing the town to be nuked. Eddie breaks from the group to join a small collection of fighting survivors who plan to wait at the center of town for evacuation, while the remainder of them make for the hospital in a national guard LAV as it is believed to have a helicopter. Unknown to them, the hospital is under attack and has become a hive for the infestation - the Predalien’s ability to implant chestburster embryos into female hosts allows the hive to be created within mere hours. A brief altercation results in Jesse panicking and fleeing - she inadvertently runs into the path of one of Wolf’s shurikens and is killed. Ricky retaliates as Wolf is knocked down an elevator shaft by an alien, dropping his plasma pistol. Ricky is impaled by the Predalien, but manages to live through the encounter as he is driven off. Dallas retrieves the plasma pistol as the group makes for the helicopter.
On the roof, Dallas stays behind briefly to fight off the aliens with the plasma pistol, until he is cornered. Wolf appears only a moment later to brawl against the aliens, leaving Dallas to escape just as the Predalien arrives and attacks Wolf. As the two extraterrestrials battle, the helicopter lifts off, carrying an injured Ricky, Dallas, Kelly and her daughter, just as a jet fighter plane drops a bomb. As the survivors await the promised airlift and fighting a losing battle with the aliens, Sheriff Morales spots the fighter plane, realising that Kelly was correct about avoiding the center of town. Both Wolf and the Predalien mortally wound each other just as the small-scale tactical nuclear weapon detonates, destroying all the survivors, the aliens, Wolf and the Predalien within its blast radius. The helicopter gets caught in the shock wave, and crash lands in a clearing.
Dallas wakes to find Kelly, Molly and Ricky still alive and outside the crashed craft. After hearing threatening noises, they find themselves surrounded by camouflaged soldiers. Dallas gives up the plasma pistol, while med-evac tends to his still injured brother; Kelly reassures her daughter that the monsters are finally gone.
The scene shifts elsewhere, to a corporate building in the U.S., where Colonel Stevens approaches Ms. Yutani. He opens the briefcase he is carrying, to reveal the plasma caster. Ms. Yutani states that the world is not ready for the new technology, while Colonel Stevens makes it clear the technology is "not for our world, is it Ms. Yutani?"
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