In the year 2077, Tech 49 Jack Harper (Tom Cruise) is one of the last drone repairmen stationed on Earth. Jack tells us that the planet was nearly destroyed sixty years ago, during a war against a race of alien invaders known as Scavengers ("Scavs"). The Scavs destroyed the moon, causing massive earthquakes and tsunamis, and then launched their invasion. They were only defeated by the use of nuclear weapons, which left most of the planet irradiated and uninhabitable. The few surviving humans migrated to a large space station called the "Tet," a massive tetrahedral space station that orbits the Earth, which is powered using energy harvested on Earth by giant ocean-borne power stations that generate fusion power from seawater before migration to Titan, one of Saturn's moons. From Tower 49, a base standing above the remains of the northeastern United States, Jack and his partner and lover Victoria "Vika" Olsen (Andrea Riseborough) work as a team to maintain the autonomous drones that defend the power stations from the few remaining Scav bandits. They receive their orders from Sally (Melissa Leo), their mission commander, who is stationed on the Tet. Jack flies recon and repair missions to the surface, while Vika supervises from Tower 49, a home at around 3000 feet (1000 meters) above the sea. The two expect to leave Earth and join the other survivors on the Tet in two weeks. Although Jack and Vika had their memories wiped five years earlier for security reasons, Jack has recurring dreams about meeting a mysterious woman at the Empire State Building before the war - which was before he was born. Jack keeps a secret retreat in a forested area he sometimes visits.
A Scav signal beacon transmitting coordinates off Earth is followed shortly by the crash of a pre-invasion spacecraft. Drones arrive at the crash site and kill most of the crew, but Jack manages to rescue a woman, Julia (Olga Kurylenko), recognizing her as the woman from his dreams. Julia says her ship — the Odyssey — was a NASA mission, the objective of which she refuses to reveal, and she and Jack retrieve the ship's flight recorder. They are captured by Scavs, who are revealed to be humans living in what remains of the Raven Rock Mountain Complex. Their leader, Malcolm Beech (Morgan Freeman), claims that the alien invasion was a lie and wants Jack to reprogram a captured drone in order to destroy the Tet by delivering a nuclear weapon powered by the Odyssey's core reactor, the reason they deorbited the Odyssey. When Jack refuses, Malcolm releases the captives but urges them to seek the truth in the so-called "radiation zone" that Jack is forbidden to enter.
On their way back to the Tower, Jack takes Julia to the ruins of the Empire State Building and asks her who she is. She reveals that she was his wife before the war. His dreams were flashbacks to the day he proposed to her on the Empire State Building's observation deck. As Jack and Julia share a loving embrace Vika watches via her video link to Jack’s ship, and when they return to the Tower she refuses them entry. When she informs Sally that she and Jack are no longer an "effective team," Sally activates a drone that kills Vika. Before the drone can kill Jack, Julia uses the weapons on Jack's ship to destroy the drone. Sally requests that Jack return to the Tet with Julia, but they flee in his ship instead, pursued by more drones. They crash in the radiation zone, where Jack comes face to face with Tech 52, a clone of himself. He fights the clone, who, upon catching sight of Julia, also begins experiencing memory flashbacks, before Jack renders him unconscious. Jack sees that Julia has been seriously wounded by a stray bullet from his struggle with Tech 52. Jack impersonates Tech 52, activating his vehicle and going to Tower 52, where he encounters a clone of Vika, and steals a med kit to help Julia.
Shocked, Jack and Julia return to Beech, who tells them the truth: the Tet is in fact an alien artificial intelligence that seized Earth to exploit the planet's resources, and Jack and Victoria are just two of many thousands of clones of their original selves (who were astronauts from 2017) created as soldiers to carry out the invasion of Earth. The Tet uses drones programmed to kill humans on sight. The survivors use old technology like stealth fighter shielding and vocal scrambling to confuse the drones (thus looking like 'scavs'). The Tet uses clones of Jack and Vika to maintain the drones, and thereby its dominance. Jack agrees to reprogram the stolen drone to destroy the Tet. When leaving the underground stronghold with the reprogrammed drone, they are attacked by three other drones. The drones enter the base and wreak havoc inside, severely damaging the reprogrammed drone and wounding Beech in the process. The humans finally manage to destroy the three drones, but are forced to find another way to deliver the nuclear bomb to the Tet. Jack proposes delivering the bomb himself. To throw off suspicion, Julia suggests that she accompany Jack, since Sally had requested him to bring her to the Tet.
During the flight, Jack listens to the Odyssey's flight recorder, which reveals that he and Victoria were originally pilots on the Odyssey research mission to Titan, which was reassigned by NASA when the Tet was discovered near Saturn. Sally was originally their supervisor at NASA mission control, with other personnel, including Julia, on board in cryogenic sleep capsules. Upon approach, the Tet drew them in using a form of tractor beam. Recognizing that capture was imminent, Jack was able to jettison the sleeping crewmembers, who orbited for sixty years in suspended animation until Beech sent the signal to recall their craft.
Jack enters the Tet, where he is met by a sentient tetrahedral structure that had adopted the persona of Sally. Jack opens the sleep capsule to reveal Beech; Julia simultaneously emerges from another sleeping capsule at Jack's secret forest retreat. The two men trigger the nuclear bomb and destroy the Tet at the cost of their own lives. The destruction of the Tet also deactivates the remaining drones around the world just as they were about to slaughter the survivors at the Scavs' underground base.
Three years later, Julia is living with her young daughter in the forest retreat on the recovering Earth. A group of survivors arrive there, and Tech 52 emerges from the group. A voice-over by Tech 52 reveals that his previous encounter had re-awakened memories of Julia, and he had searched for her since the Tet's destruction. Having the same latent memories as Tech 49, he then reunites with "his" family.
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