In 2004, a satellite detects a mysterious heat bloom beneath Bouvetøya, an island about one thousand miles north of Antarctica. Wealthy industrialist Charles Bishop Weyland (Lance Henriksen) assembles a team of scientists to investigate the heat source and claim it for his multinational communications company, Weyland Industries. The team includes archaeologists, linguistic experts, drillers, mercenaries, and a guide named Alexa Woods (Sanaa Lathan).
As a Predator ship reaches Earth's orbit, it blasts a shaft through the ice towards the source of the heat bloom. When the humans arrive at the site above the heat source, an abandoned whaling station, they find the shaft and descend beneath the ice. They discover a mysterious pyramid and begin to explore it, finding evidence of a civilization predating written history and what appears to be a sacrificial chamber filled with human skeletons with ruptured rib cages.
Meanwhile, three Predators land and kill the humans on the surface, making their way down to the pyramid and arriving just as the team unwittingly powers up the structure. An Alien queen awakens from cryogenic stasis and begins to produce eggs, from which facehuggers hatch and attach to several humans trapped in the sacrificial chamber. Chestbursters emerge from the humans and quickly grow into adult Aliens. Conflicts erupt between the Predators, Aliens, and humans, resulting in several deaths. Unbeknownst to the others, a Predator is implanted with an Alien embryo.
Through translation of the pyramid's hieroglyphs the explorers learn that the Predators have been visiting Earth for thousands of years. It was they who taught early human civilizations how to build pyramids, and were worshipped as gods. Every 100 years they would visit Earth to take part in a rite of passage in which several humans would sacrifice themselves as hosts for the Aliens, creating the "ultimate prey" for the Predators to hunt. If overwhelmed, the Predators would activate their self-destruct weapons to eliminate the Aliens and themselves. The explorers deduce that this is why the current Predators are at the pyramid, and that the heat bloom was to attract humans for the purpose of making new Aliens to hunt.
The remaining humans decide that the Predators must be allowed to succeed in their hunt so that the Aliens do not reach the surface. As the battle continues most of the characters are killed, leaving only Alexa and a single Predator to fight against the Aliens. The two form an alliance and use the Predator’s self-destruct device to destroy the pyramid and the remaining Aliens. Alexa and the Predator reach the surface, where they battle the escaped Alien queen. They defeat the queen by attaching its chain to a water tower and pushing it over a cliff into the water, dragging the queen to the ocean floor. The Predator, however, dies from its wounds.
A Predator ship uncloaks and several Predators appear. They collect their fallen comrade and present Alexa with one of their spear weapons in recognition of her skill as a warrior. As they retreat into space, a chestburster erupts from the dead Predator. It appears to be an Alien/Predator hybrid with the characteristic mandibles of both creatures.