In 2011, astronauts Brian Harper, Jocinda "Jo" Fowler, and newcomer Marcus are on a Space Shuttle mission to repair a satellite. A mysterious swarm of alien technology attacks the orbiter, killing Marcus and knocking Jo unconscious before tunneling into the surface of the Moon. Brian, the only witness to the swarm, returns the crippled shuttle to Earth, but his story is dismissed and he is fired from NASA.

Ten years later, conspiracy theorist K.C. Houseman, who believes the Moon is an artificial megastructure, secretly uses time on a research telescope. He discovers the Moon's orbit is veering closer to Earth, and tries to share his findings with the disgraced Brian. NASA also discovers the anomaly, but K.C. goes public on social media, leading to global panic. Jo is now NASA's deputy director, launching a spacecraft on an SLS Block 1 rocket to investigate the abnormality. The same alien swarm attacks, killing all three lunar astronauts after they drop a probe into a kilometers-deep artificial shaft that has opened up on the Moon's surface.

As lunar orbit deteriorates, the Moon falls closer and closer to Earth, causing seismic and gravitational disturbances. Jo meets former NASA official Holdenfield, who reveals that Brian was discredited due to a NASA coverup dating back to Apollo 11; during the first moon landing, a two-minute radio blackout was meant to conceal evidence of pulsating lights on the surface. Apollo 12 also revealed that the Moon is hollow, and a military EMP device created to kill the swarm was abandoned for budgetary reasons.

With help from her ex-husband General Doug Davidson, Air Force Chief of Staff, Jo requisitions the EMP and rescues retired Space Shuttle Endeavour from a museum to serve the new mission: to correct the Moon's orbit and destroy the swarm. Brian, K.C., and Jo launch with the EMP, narrowly escaping to orbit as a tsunami destroys Vandenberg Air Force Base.

They reach the interior of the Moon, revealed to be a Dyson sphere powered by a white dwarf at its center. The Dyson sphere's AI operating system explains to Brian that billions of years ago, humanity's technologically advanced ancestors were eradicated by a rogue AI; they built the Moon as a Interstellar ark to create and seed life on Earth, but the swarm — one of the malicious AIs — discovered the Moon and is siphoning energy from its power source, destabilizing its orbit.