The film begins on Mars in 2046, in a research facility at a location known as Olduvai where scientists are running for their lives. One by one, they are grabbed and pulled into the darkness by some unseen monster, screaming in terror. Eventually, all but a Dr. Carmack are killed. As the doctor sends an SOS rescue signal, the "thing" breaks through the door, growls and stares at the doctor, and the scene fades out. On Earth, a team of elite special ops Marines has their leave interrupted by Sarge (The Rock), who has received a call from Olduvai. As the men suit up, Sarge pulls aside one of his men, John "Reaper" Grimm (Karl Urban), and asks him not to go because his sister is on the station. Reaper suits up anyway, and their team is deployed to Mars via a teleportation device called the Ark, located in Nevada. The Ark was discovered in 2026, and for twenty years scientists have been trying to discover who built it, and why. Upon arriving at the Mars research facility of the Union Aerospace Corporation (UAC), they meet a victim of the Ark travel, Pinky (Dexter Fletcher), who had his legs severed by the Ark during an early attempt to use it. They meet up with Dr. Samantha Grimm (Rosamund Pike), Reaper's sister, who explains the situation.
Their mission is simple: eliminate the threat, secure the facility, and retrieve UAC property. They set off and quickly locate Dr. Carmack, who is disturbed to the point of tearing off his own ear. They return him to the lab, and Dr. Grimm tries to sedate him. John converses with his sister and learns that they have discovered humanoid remains on Mars that contain a 24th chromosome that made the creatures superhuman, invulnerable to disease and with the ability to regenerate quickly. Meanwhile, the Marines continue to explore the facility, encountering strange creatures intent on killing them. One of the creatures, an imp, succeeds in slaying one of the Marines, but is promptly killed and brought to Dr. Grimm. From blood samples taken from two hostile creatures, it is determined that their genetic makeup has been altered by the addition of the 24th chromosome; however, the injected chromosome seems to "choose" whether or not the result causes the person to be superhuman or a monster, using what Dr. Grimm believes to be the unmapped 10% of the human genome, and latching onto what could be a gene that predestines people to be evil. Consequently, the chromosome is classified as an infection, which is later spread by the projectile tongues of those infected.
Through multiple attacks by the imps, the squad is reduced to just Sarge, Reaper, The Kid (Al Weaver), Duke (Razaaq Adoti) and Dr. Grimm. They realize that despite their best efforts, a larger monster called "The Baron" (presumed to be the original infection) has escaped to Earth through the Ark. Before leaving, Sarge takes the Bio Force Gun (BFG9000 of Doom fame), humorously dubbing it the "Big Fucking Gun".
On Earth, the group finds the UAC facility full of bodies. Sarge orders that everyone breathing must be killed to prevent the infection from spreading. The Kid finds a group of living, non-infected humans and reports this to Sarge. He argues that the order should be rescinded ("Go to hell"), but Sarge responds by saying that violating the CO's order is punishable by death and shoots The Kid for insubordination. The group continues through the facility until Duke is killed during a major assault by zombies. In addition to Duke's death, and Sarge being dragged away by the zombies, Reaper is hit by a ricocheting bullet. Consequently, to save his life, Dr. Grimm injects Reaper with Chromosome 24. Rather than becoming one of the monsters, Reaper is endowed with superhuman strength and speed, as well as near instantaneous healing ability.
Following Reaper's change, the movie takes on its first-person shooter perspective, reminiscent of Doom 3. In a span of a few minutes, Reaper slays an array of monsters, including the Baron, several imps, a fair amount of zombies, and Pinky (who has appropriately mutated into a Pinky Demon).
Switching back to a standard camera angle, Reaper emerges at the exit of the facility. Bodies are scattered everywhere, and a blue burning hole in the wall, the mark of a BFG blast, is still settling. Near this hole, Reaper encounters Sarge and an unconscious Dr. Grimm lying on the floor. Reaper asks Sarge what happened to the non-infected survivors, to which he replies that he took care of it: he has killed them. Reaper then notices the same injury on Sarge that Dr. Carmack had before he turned into an Imp. After Dr. Grimm escapes to safety, the two Marines face off, Reaper having exhausted most of his current clip and Sarge similarly limited to a single BFG round. After ineffectively using this ammunition, the two engage in hand-to-hand combat, which favors Sarge. Sarge's transformation begins to manifest during the battle, making him that much stronger. Reaper prevails by throwing Sarge into the Ark, followed by a grenade. The Ark locks down after this, preventing further travel and appearing to seal the fate of both Sarge and the UAC Mars facility. Reaper then retrieves Dr. Grimm, who is just visibly conscious but unable to stand or walk, and holds her in his arms as he uses the elevator to return to the Earth's surface.
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