Psychiatrist Dr. Hill is called to the emergency room of a California hospital, where a screaming man is being held in custody. Dr. Hill agrees to listen to his story. The man identifies himself as a doctor, and recounts, in flashback, the events leading up to his arrest and arrival at the hospital.
In the nearby town of Santa Mira, Dr. Miles Bennell sees a number of patients apparently suffering from Capgras delusion – the belief that their relatives have somehow been replaced with identical-looking impostors. Returning from a trip, Miles meets his former girlfriend, Becky Driscoll, who has recently come back to town after a divorce. Becky’s cousin Wilma expresses the same fear about her Uncle Ira, with whom she lives. Psychiatrist Dr. Dan Kauffman assures Bennell that these cases are merely an “epidemic of mass hysteria”.
That evening, Bennell’s friend, Jack Belicec, finds a body with his exact physical features, though it appears not fully developed; later, another body is found in Becky’s basement that is her exact duplicate. When Bennell calls Kauffman to the scene, the bodies have mysteriously disappeared, and Kauffman tells Bennell that he is falling for the same hysteria.
The following night, Bennell, Becky, Jack, and Jack’s wife Teddy again find duplicates of themselves, emerging from giant seed pods in Bennell’s greenhouse. They conclude that the townspeople are being replaced while asleep with exact physical copies. Miles tries to make a long-distance call to federal authorities for help, but the phone operator claims that all long-distance lines are busy. Jack and Teddy drive off to seek help in the next town. Bennell and Becky soon realize that all of the town’s inhabitants have been replaced and are devoid of humanity. They hide at Bennell’s office for the night, vowing to stay awake.
The next morning, from the office window, Bennell and Becky watch as truckloads of the giant pods arrive in the town center. They listen as Dumke directs the others to take them to neighboring towns to be planted and used to replace their populations. Kauffman and Jack, both of whom are now also “pod people”, arrive at Bennell’s office with new pods for Becky and Bennell. They reveal that an extraterrestrial life form is responsible for the invasion; the pods, capable of replicating any life form, traveled through space and landed in a field. After their takeover, they explain, humanity will lose all emotions and sense of individuality, creating a simplistic, stressless world.
After scuffling with and knocking out Kauffman, Jack and Dumke, Bennell and Becky escape the office. Outside, they pretend to be pod people, but Becky screams at a dog that is about to be hit by a car, exposing their humanity. A town alarm is sounded and they flee on foot, pursued by a mob of “pod people”.
Exhausted, they manage to escape and hide in an abandoned mine outside town. Later, they hear music and Bennell leaves Becky briefly to investigate. Over a hill, he sees a large greenhouse farm with giant seed pods, being grown by the thousands and loaded onto trucks. Bennell returns to tell Becky, and upon kissing her he realizes, to his horror, that she fell asleep and is now one of them. Becky sounds the alarm as he runs away. He is again chased by the mob, and eventually finds himself on a crowded highway. After seeing a transport truck bound for San Francisco and Los Angeles filled with the pods, he frantically screams at the passing motorists, “They’re here already! You’re next! You’re next!”
The flashback ends, and back at the hospital, Dr. Hill and the on-duty doctor dismiss Bennell’s story as a lunatic rambling. As the doctors step into the hall to discuss, a truck driver is wheeled into the emergency room after being badly injured in an accident. The orderly tells the doctors that the man had to be dug out from under a load of giant seed pods. Finally believing Bennell’s story, Dr. Hill calls for all roads in and out of Santa Mira to be barricaded, and alerts the FBI.