Decades-old found footage from NASA's abandoned Apollo 18 mission, where two American astronauts were sent on a secret expedition, reveals the reason the U. S. has never returned to the moon. In December, 1973, the crew of the previously-cancelled Apollo 18 mission is informed that the mission is a go, though it has now been deemed a top secret Department of Defense mission. Commander Nathan Walker (Lloyd Owen), Lieutenant Colonel John Grey (Ryan Robbins) and Captain Benjamin Anderson (Warren Christie) are launched towards the Moon to place detectors to alert the United States of any impending ICBM attacks from the USSR.
Grey remains in orbit aboard the Freedom Command/Service module while Walker and Anderson land on the moon in the lunar module Liberty. While planting one of the detectors, the pair take samples of moon rocks. While attempting to sleep, the pair hear noises outside and a camera captures a small rock moving nearby. Houston (Andrew Airlie's voice) claims the noises are interference from the ICBM detectors. Anderson finds a rock sample on the floor of Liberty despite having secured the samples. During further exploration they discover footprints that lead them to a Soviet LK lander nearby, finding it functional but blood-stained.
Anderson follows tracks leading into a dark crater and finds a dead cosmonaut. Walker queries Houston about the Soviet presence but is told only to continue with the mission. The following day the pair find that the flag they had planted is missing. Their mission complete, the crew prepares to leave the Moon but the launch is aborted when Liberty suffers violent shaking. An inspection reveals extensive damage to Liberty and non-human tracks that Walker cites as evidence of extraterrestrial life. Walker feels something moving inside his spacesuit and helmet and is horrified as a spider-like creature crawls across the inside of his helmet. Walker disappears from view and Anderson finds him unconscious outside of Liberty.
Walker later denies the events. A wound is discovered on Walker's chest; Anderson feels, and removes, a Moon rock embedded within him. The pair find themselves unable to contact Houston or Grey due to increased levels of interference from an unknown source. Anderson speculates that the true intention of the ICBM warning devices is to monitor the aliens. The pair also increasingly wonder if the devices are the source of the interference; Houston had assured them that this was not so.
Walker shows signs of a developing infection around his wound and he becomes increasingly paranoid. The mission cameras capture the rock samples moving around in the interior of Liberty, revealing that the aliens are the moon rocks (or indistinguishable from the real rocks). Increasingly delusional, Walker attempts to destroy the cameras within Liberty but accidentally damages the system controls, causing Liberty to depressurize. Realizing the Soviet LK is their only source of oxygen, the pair travel to the LK lander in their lunar rover. Along the way, Walker attempts to run away, believing he should not leave the Moon because of the risk of spreading the infection to Earth.
Anderson crashes as he attempts to stop Walker. Anderson awakens and tracks Walker, finding him at the crater where they found the cosmonaut. Walker is pulled into the crater by the creatures. Anderson gives chase, using his strobe light to illuminate the area. The rocks start to sprout their spider-like legs, causing Anderson to flee to the Soviet LK. Using its radio he makes contact with USSR Mission Control who connect him to the United States Department of Defense. The deputy secretary of the department informs Anderson that they will not allow him to return to Earth, admitting they are aware of the situation and fear he is also infected. Anderson manages to contact Grey and they make arrangements for Anderson to return to Freedom.
Anderson prepares the lander for launch but it is attacked by Walker. Before Walker can breach the vehicle, he is swarmed by the creatures, which crawl into his helmet and cause his blood to splatter onto the lander. Anderson launches the LK lander successfully with the intent of arriving near Freedom and entering it via spacewalk. Grey is informed that Anderson is infected. Grey is ordered to abort Anderson's rescue or communication will be ceased, rendering him unable to return to Earth.
Inside the lander, the reduced gravity causes small rocks within the Soviet craft to float. Anderson realizes with horror that some of the rocks are actually alien creatures. Anderson is attacked and infected by the creatures, preventing him from controlling the vehicle, leaving it headed toward Freedom. Grey yells to Anderson that he is coming in too fast. The space footage ends abruptly, implying a collision. The footage cuts to before the pilots' mission, showing them having a barbecue with friends and family.
The "official" fate of the astronauts is given, describing them as having died in various accidents that left their bodies unrecoverable. An epilogue explains that many of the rock samples returned from the previous Apollo missions are unaccounted for..