Matthew Bennell (Donald Sutherland) is a San Francisco health inspector who, with his friend and colleague Elizabeth Driscoll (Brooke Adams), discovers that people are being replaced by replicas grown from plantlike pods. The replicas are near-perfect duplicates with the same memories and appearance as the original person, but are emotionless. The pods are able to duplicate humans only when they are asleep, and the original human bodies disintegrate after the duplicate is fully formed. The pod people then work together to spread more pods so more people can be replaced with the aim of eliminating the entire human race. The film follows a small group of people who discover the plot and try to stop it, or at least escape. However, it proves increasingly difficult as they are unable to determine who can be trusted.
The film opens out in deep space where a race of gelatinous creatures abandon their dying world. Pushed through the universe by the solar winds, they make their way to Earth and land in San Francisco. Some fall on plant leaves, assimilating them and forming small pods with pink flowers. Elizabeth is one of several people who brings a flower home. The next morning, Elizabeth's husband, Geoffrey Howell (Art Hindle), suddenly becomes distant and she knows something is wrong. Matthew suggests that she see his friend Dr. David Kibner (Leonard Nimoy), but they discover the problem is far more widespread.
Dr. Kibner suggests that Elizabeth wants to believe that Geoffrey has changed because she is looking for an excuse to get out of their relationship. Meanwhile, Matthew's friend Jack Bellicec (Jeff Goldblum), a struggling writer who owns a mud bath with his wife Nancy (Veronica Cartwright), discovers a deformed body on one of the beds and calls Matthew to investigate. Noticing that the body (which has adult features but lacks distinguishing characteristics) bears a slight resemblance to Jack, Matthew breaks into Elizabeth's home and finds a nearly complete double of her in the bedroom garden; he is able to get Elizabeth to safety but the duplicate body disappears when he returns with the police. Matthew realizes that what is happening is extraterrestrial, not realizing that Dr. Kibner has also been changed. He calls several state and federal agencies, but they all tell him not to worry. In addition, people who earlier claimed that their loved ones had changed seem to have been converted as well. That night, Matthew and his friends are nearly duplicated by the pods while they sleep. The pod people try to raid Matthew's house, but the humans are able to slip away. During this, they discover that the pod people emit a piercing shrill scream once they learn someone is still human among them.
Jack and Nancy sacrifice themselves to a crowd of pursuing pod people as a distraction, to give their friends enough time to escape. Matthew and Elizabeth are chased across San Francisco, until they are eventually found by the doubles of Jack and Dr. Kibner at the Health Department. They are both injected with a sedative to help them sleep. However, the couple is able to overpower them and escape the building. They run into Nancy in the stairwell, who has discovered a way to evade the pod people by hiding all emotion. Outside, Matthew and Elizabeth are exposed as human when Elizabeth screams after seeing a mutant dog with a man's face (caused by Matthew stepping on and damaging the dog's pod earlier). They flee, leading them to discover a giant warehouse at the docks where the pods are grown. After Matthew and Elizabeth profess their love for each other, they hear "Amazing Grace" being played nearby. Matthew goes out to investigate, only to discover a cargo ship being loaded with hundreds of pods.
Matthew returns to find that Elizabeth has fallen asleep. While trying to wake her in his arms, her body crumbles to dust and Elizabeth's naked double arises behind him, asking him to fall asleep as well. With no one left, Matthew attempts to destroy the pod-growing facility by cutting the overhead lights. Within moments, the entire warehouse is on fire and the unhatched pods begin to die. He is pointed out by Elizabeth's double and hides under a pier while the pod people frantically search for him. The next day, Matthew passively watches dozens of children being led into a dark theater to be replaced. At the Health Department, Elizabeth and all their co-workers now stand silently, listening for their instructions to spread the invasion across the West Coast. While walking towards city hall, he is spotted by Nancy, who survived the previous night. Thinking he is human, she calls his name, to which Matthew responds by pointing to her and emitting the piercing pod scream.