In deep space, a race of gelatinous creatures abandon their dying world. Pushed through space by the solar wind, 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.
The Pod People are aliens that appear to be perfect copies of the persons replaced, but devoid of any human emotion.
Matthew realizes that what is happening is extraterrestrial, and that people are being replaced by copies while they sleep. Matthew calls several state and federal agencies, but they all tell him not to worry. In addition, people who had earlier claimed that their loved ones had changed seem to have been converted as well, including (unbeknownst to him) Dr. Kibner, and repudiate their earlier claims of their loved ones being imposters.
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 he and his friends are able to escape. During this, they discover that the pod people emit a shrill scream once they learn someone is still human among them.
Jack and Nancy create a diversion within a crowd of pursuing pod people to give Matthew and Elizabeth time to escape. Matthew and Elizabeth are chased across San Francisco. They are eventually found by the doubles of Jack and Dr. Kibner at the Health Department building. Kibner's double tells them that what the alien species is doing is purely for survival and that they are even doing humanity a favor by ridding them of emotion. Matthew and Elizabeth are injected with a sedative to make them sleep. However, having already taken a large dose of speed, the couple overpower them and escape the building.
In the stairwell, they find Nancy, who has learned 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. They flee, and discover a giant warehouse at the docks where the pods are grown. After Matthew and Elizabeth profess their love for each other, 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. He tries to wake her, but her body crumbles to dust and her naked double arises, telling him to embrace his fate and sleep. Matthew returns to the warehouse and sets it on fire, destroying many pods. He hides from the pod people under a pier, but they know he will have to fall asleep eventually.
The next morning, Matthew watches dozens of children being led into a theater to be replaced. At work he sees Elizabeth, but she is completely oblivious to him. While walking towards City Hall, he is spotted by Nancy, who has avoided conversion into a pod person. She calls his name, to which Matthew responds by pointing to her and emitting the piercing pod scream. Realizing that Matthew is now a pod person, Nancy, now the only human left in the city, screams in helpless terror.