A species of gelatinous creatures, having abandoned their dying planet and traveled to Earth, land in San Francisco. They infiltrate Earth's ecosystem, latching onto plant life and taking the form of small pods with fragrant pink flowers. Elizabeth Driscoll, a laboratory scientist at the San Francisco Health Department, brings one of the flowers home, where she lives with her boyfriend, Geoffrey. Leaving the flower on their bedside table, she awakens the next morning to discover Geoffrey behaving strangely cold and distant.
Elizabeth's colleague, Matthew Bennell, suggests she speak to his psychiatrist friend, David Kibner, who is holding a book-signing party to promote his new self-help book. As Elizabeth and Matthew drive to the bookstore, a hysterical man on the road screams to them, shouting "They're coming! You'll be next!" before being chased away by a mob of people and then hit by a car. At the bookstore, while Matthew tries to report the accident to apparently unbelieving authorities, Elizabeth asks David for help regarding Geoffrey. David theorizes that people are using various pretexts to cope with their highly stressed lives, and suggests that Elizabeth is simply using the belief that Geoffrey is behaving differently as an excuse to end their relationship. Despite other people having also complained that their loved ones had become strange, she contemplates that David may be right. Meanwhile, Matthew's friend, Jack Bellicec, calls Matthew to investigate when a grotesque body covered in fibers, which resembles Jack, is found in his wife Nancy's mud baths. Sensing danger with these odd occurrences, Matthew goes to Elizabeth to warn her. After breaking into her house, he finds Elizabeth in a deep sleep, but also discovers a semi-formed duplicate of her in the bedroom. Suspecting Geoffrey's involvement, Matthew takes Elizabeth home with him, but when he returns later with the police, the duplicate body is gone.
The following night, Matthew and his friends are nearly duplicated as they sleep, by four pods in Matthew's garden. The aliens gestate inside the pods, which grow to around 3 ft (1 m) in length before breaking open and spawning a human duplicate that grows rapidly. The pods duplicate humans while they are sleeping in the immediate vicinity, copying not just their physical characteristics, but also their memories. Once the duplication is complete, the original human dies and disintegrates, and the alien "pod person" takes their place. Matthew calls the police, but soon realizes that the department has been infiltrated. They have also begun tracking him through the phone lines, alerting others to the group's location. Matthew destroys his own semi-formed duplicate before escaping with the others, pursued by the aliens, who emit a shrill scream when they discover a human being among them, drawing other aliens nearby. Cornered at a dead-end road, Jack and Nancy break away and create a distraction, allowing Matthew and Elizabeth to hide and eventually escape back into the city. There, the pair takes refuge in the health department, where they each ingest a large dose of speed to prevent themselves from falling asleep. Again tracked through the phone lines, they are soon captured by Jack and David, who have been duplicated. Matthew and Elizabeth are injected with sedatives while being told of the aliens' intentions for survivability, but due to their previous consumption of speed, they do not fall asleep. They are able to kill Jack's duplicate and lock David in a refrigerated room, and escape.
Matthew and Elizabeth reunite with Nancy, who has learned to evade the aliens by hiding her emotions and blending in with them. The two follow her example, but their cover is blown when Elizabeth screams at the sight of a mutant dog with a human head. They separate from Nancy amid the chaos, and quickly board a truck en route to Pier 70, where the aliens are cultivating more pods, intending to transport them to other cities. Matthew scouts around for a way to flee the area, but the ship he hopes they can get away on is also revealed to be carrying pods to distant locations. Matthew returns to Elizabeth, but she has fallen asleep and when he embraces her she disintegrates in his arms. Moments later the naked body of a duplicated Elizabeth appears, and she speaks enticingly to him to try to get him to join her. Pursued by the shrieking duplicate Elizabeth, he breaks into the docks' warehouse and burns down the building, destroying hundreds of pods. He flees and hides under a bridge, exhausted, as the aliens try to find him. One of his pursuers tells another he has to fall asleep eventually.
Matthew, walking like an alien and showing no outward signs of emotion, returns to work at the health department. He watches several schoolchildren being taken for duplication, and more pods being prepared for the remaining West Coast cities.
In the final scene, Matthew (Donald Sutherland) demonstrates the characteristic pose by which the "pod people" identify unconverted humans.
At the end of the day, as he heads towards City Hall, he hears his name being called. Nancy, still on the loose, quietly approaches him and attempts a hushed conversation. To her horror he points at her and emits an earsplitting shriek. He has been replaced by a pod.
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