On an unidentified planet, a strange lifeform in the shape of gel-like spores drifts up into the atmosphere, where it moves slowly through space, drifting until it reaches Earth. The spores enter the atmosphere and are swept downward, emerging in a rainstorm in San Francisco. On the ground, the spores begin to develop, growing on leaves of earthly plants and taking the shape of small pods with a pink flower in the middle.
Elizabeth Driscoll (Brooke Adams) notices one of the pods, taking it back to the home she shares with her boyfriend, Geoffrey. Unable to find the flowering pod in any of her botany books, she hesitantly identifies her new find as a cross-breeding of two different species, a "grex."
Matthew Bennell (Donald Sutherland) is an inspector for the health department who uncovers unsanitary conditions at a French restaurant. As he threatens the owner with indictment over finding rat droppings in the food, the other employees quietly slip out to the parking lot and smash Matthew's windshield with a bottle of wine.
Matthew is cold and calculating, refusing to let them see his frustration at finding his car vandalized, but when he gets home he calls Elizabeth. They work together at the health department, and Matthew jokes with her about what happened to him at the restaurant.
As Elizabeth goes to bed, she forgets about the weird pod, which has suddenly sprouted roots in the glass of water she keeps it in next to their bed. When Elizabeth wakes the next morning, Geoffrey is already awake and dressed, cleaning up the remains of the glass of water next to the bed, as well as some other, unidentifiable mess (resembling some kind of dust).
His behavior is strange, and she follows him downstairs as he takes a plastic garbage bag out to a waiting dump truck. At work, she confides to Matthew that Geoffrey is acting strange.
Later that night, Elizabeth tries to talk it over with Geoffrey but he ignores her, instead telling her that he's going out and giving her no explanation. Elizabeth touches him intimately and recoils from his emotionless response. Elizabeth rushes over to Matthew's house and insists that Geoffrey is no longer Geoffrey. On the outside he looks the same, but inside he is different. Matthew hears her out but calms her by cooking a good meal and letting her vent.
The next day, Matthew hears a strange story from the owner of the Chinese laundry he patronizes: his wife is not his wife. Later he finds Elizabeth at the health department offices, shaken and obviously distraught. She reveals that she has been following Geoffrey during that day and has seen him having brief meetings with strangers, all of them passing unidentifiable parcels among themselves.
She is convinced that there is some sort of conspiracy afoot and that Geoffrey is a part of it. Matthew wants to take her to meet his friend, a renowned psychologist named David Kibner (Leonard Nimoy). Kibner has written a number of popular books, the latest of which has just been published, and Matthew takes Elizabeth to a book signing party at a local bookstore so she can meet Kibner personally.
While stopped at a traffic light, a strange man (Kevin McCarthy, the star of the original movie) suddenly falls onto Matthew's car, screaming and pounding at the windows, warning "They're coming! Something terrible! You're in danger!" Before they can react, another vehicle comes along and strikes the man dead.
Strangely, the crowd of people around him seem to not be affected by what has happened at all, not even the motorcycle policeman who arrives on the scene. (Unnoticed by Matthew and Elizabeth, there are one or two others down the streets and sidewalks running from groups of other people chasing them.)
At the book party that evening, Matthew and Elizabeth meet up with Jack Bellicec (Jeff Goldblum), a friend of Matthew's. Matthew tries to phone in a report to the police about the accident, but he meets with strange resistance. Elizabeth becomes entranced by an extremely upset woman who is insisting to Kibner that her husband is an impostor.
Kibner calms the woman somewhat before sending her on her way with her husband, but Elizabeth urges the woman to contact her at the health department because she knows what she is trying to say.
Finally, Matthew is able to introduce Elizabeth to Kibner, who admits that over the past few days, other people have been coming to him with the same story that Elizabeth is telling. The patients tell him that someone close to them is acting strange and seems like an impostor; the patients seem to get over it quickly and change their story. Kibner suggests that it is a result of the emotional isolation people feel in modern relationships, but even Matthew notices that Kibner doesn't seem to be listening to what Elizabeth is really saying. Matthew takes Elizabeth home and she finds a plant waiting for her; a card indicates it's a gift from Geoffrey.
Jack returns to his wife, Nancy (Veronica Cartwright), who runs a mud bath facility. Jack is frustrated over not getting a chance to read his poetry at Kibner's book party, and he goes into the baths to relax. Nancy interacts with a strange patron name Mr. Gianni, who has given her a plant just like the one Geoffrey left for Elizabeth. When Nancy begins closing up for the evening, she notices someone lying under a sheet and thinks it is Jack. Removing the sheet, she is startled to find a strange form underneath.
It resembles a man, but lacks distinctive features, and is covered with white tendrils. Jack, who was sleeping nearby, suddenly appears and Nancy strikes him accidentally, giving him a nosebleed, and the shape on the table begins to bleed, too.
They call Matthew and urge him to come over to examine the phenomenon, and when he realizes something terribly strange is happening, he remembers Elizabeth. Unable to reach her by phone, Matthew goes over to her house, and while Geoffrey sits listening to headphones, Matthew breaks into the house and retrieves a sleeping Elizabeth from the house.
Before taking her from her bed, Matthew is shocked to see a duplicate of her body lying nearby, covered in the same fibers as the body at the baths. Back at the baths, Jack falls asleep again and the body begins to take on his features, until Nancy wakes him up again. Matthew and Elizabeth return to the baths and summon Kibner, but the body has apparently vanished. Likewise, Matthew reports Elizabeth's "other body" to the police, but when they return to the house she shares with Geoffrey, nobody is able to find a body.
Kibner quiets the police and Geoffrey seems unconcerned that his girlfriend refuses to come home and is spending the night with Matthew. Converging at Matthew's house, the small group forms their hypothesis: somehow, people are being duplicated, and these alternate bodies are appearing to take their places. Kibner is skeptical and tries to talk them out of their ideas, but finally leaves; unseen by the others, he gets into a car with two other "conspirators," including Geoffrey.
All day, Matthew tries to get others to listen to him about what's going on. He makes phone calls, has meetings, and tries to find anybody who will take him seriously. Similarly, the woman who was so upset at the bookstore turns up at the health department and tells Elizabeth that she's alright now. That night, the Bellicecs stay at Matthew's. Kibner gives Elizabeth a mild sedative to help her sleep, and leaves. The entire group falls asleep except for Nancy.
As they sleep, four pods in Matthew's garden release white tendrils that attach to the sleeping people, and they soon burst forth with embryonic life, somehow duplicating their victims. Before the transformation is complete, Nancy revives Matthew. Together they wake the others, and Matthew tries to call for help. The telephone operators already know who he is, addressing him by name. The power goes out, and they see a horde of pod people rushing up the hill to Matthew's house.
As the others escape out the back, Matthew leaves the yard, smashing in the head of his own duplicate with a hoe. Near the docks, the group appears to be cornered behind a group of shipping crates, but Jack sacrifices himself, rushing out along the dock and getting the pod people clones to give chase. Nancy runs off after him, and Matthew and Elizabeth are on their own.
They attempt to take a taxi out of town, but the sinister looking cab driver (Don Siegel, the director of the original movie) drives them to a police roadblock that is arresting people attempting to leave the city. Matthew and Elizabeth find that they cannot escape San Francisco; the pod people are everywhere, even spreading pods right out in the open as they now apparently outnumber humans. Taking refuge in the dark offices of the health department, they find speed pills in someone's desk and take as much as they can in order to keep themselves awake.
However, they are found out by none other than Jack, who has returned with Kibner, both of them pod people. Kibner gives them a sedative. He explains that they will be reborn into a new world without emotions or complications, thanks to the alien life form that has taken root on Earth, but Matthew and Elizabeth manage to overpower both of them, killing Jack and locking Kibner in a freezer. On the way out of the building, they encounter Nancy in a stairwell; she is still human.
Nancy reveals that she and Jack were separated, but she has discovered a way to move among the pod people: by refusing to show emotion. The three of them leave the health department right out in the open, but Elizabeth is startled by a bizarre pod hybrid that has mutated into a dog with a human head. An elderly pod lady notices it and makes a high-pitched scream, which seems to be a way by the pod people to call out to others of a human in their mist.
Nancy once again gets separated from Elizabeth and Matthew, who are identified as human (Type-H as referred by the pod people) and chased throughout the city. Making their way to the docks, Matthew and Elizabeth discover a a greenhouse where thousands of pods are being cultivated. Elizabeth, hindered by a twisted ankle and lack of sleep, feels as if she can't go on much further without sleep.
Matthew goes to investigate the sounds of "Amazing Grace" coming from one of the ships, leaving Elizabeth hidden among some tall grass. Matthew is horrified to see huge palettes of pods being loaded onto the ships; the spiritual is simply a random radio broadcast, as the station is changed, the ship helmed by pod people ready to take the alien presence to other areas of the world.
When Matthew returns to Elizabeth, he finds her asleep, and he is unable to wake her. As he holds her in his arms, Elizabeth's body crumbles into a husk, and her nude clone appears in the grass. The pod Elizabeth tells Matthew that everything is alright; the conversion is painless, and good. She encourages him to sleep, but her voice is hard and cold. Matthew runs, slipping into the greenhouse facility.
He makes his way to the steep scaffolding and after taking a fire axe, beings wreaking havoc among the pods, dropping electrical lighting rigs onto them until the entire place is in flames and the unborn pods are burned. But the fire alarm is sounded, and the pod people pursue him, including the newly converted Elizabeth. Matthew slips away from them, hiding under a dock. He hears them talking amongst themselves and one of them says: "He can't get far, he has to sleep sometime."
Matthew knows that they are right. The next day, Matthew goes through the motions of his job, staring blankly at his co-workers. He sees Elizabeth in the hallways of the building but they do not acknowledge one another. Outside, Matthew sees schoolbuses of children from Santa Barbara, L.A. and other areas of California being taken to a theater for their conversion. A while later, Matthew is walking along a deserted street towards the City Hall building and hears a voice calling to him.
Turning around, he sees the still-human Nancy across the street. As she crosses the street to meet him, Matthew's face twists into a grimace and he points at her, screaming an alien scream to alert the other pod clones to her presence. Nancy screams realizing, too late, that Matthew is now a pod person as the camera zooms into his mouth and the screen fades to black.