An apparently delusional and paranoid Dr. Miles Bennell (Kevin McCarthy) has been arrested on a California highway and taken to a local hospital's psychiatric ward. There he tells a psychiatrist, Dr. Hill (Whit Bissell), and the attending physician, Dr. Bassett (Richard Deacon) his fantastic story.
Several days earlier, Miles had been called home to Santa Mira from a medical convention. His nurse, Sally Withers (Jean Willes) told him that several patients had come in frantically insisting that their relatives and friends were not who they seemed to be. On the way to the office, Miles and Sally nearly ran over young Jimmy Grimaldi (Bobby Clark) who was fleeing from his mother (Eileen Stevens). Mrs. Grimaldi says Jimmy simply didn't want to go to school. Miles was sad to see that the Grimaldis had shut down their vegetable stand because it was too much work.
Later, at his office, Miles learned that many of the patients begging for his return claimed they no longer needed his services. A former girlfriend, Becky Driscoll (Dana Wynter) stopped by. She told him that her cousin, Wilma (Virginia Christine), insisted that her father, Ira (Tom Fadden), wasn't who he seemed to be. Miles agreed to visit Wilma later. Miles and Becky chatted, revealing that they both had recently divorced. After lunch, Jimmy Grimaldi was brought to Miles's office by his grandmother. He insisted that his mother was not really his mother. Suspicious, Miles gave the boy a sedative and told his grandmother to keep the boy at her house that night.
Miles and Becky visited Ira and Wilma. Miles admitted his examination of Ira led him to conclude that it was indeed Ira. Wilma insisted that although nothing physically or mentally seemed different about him, his emotional connection to her was wrong. Wilma agreed to see a psychiatrist to discuss her concerns. That night, Becky and Miles went to dinner and encountered the town psychiatrist, Dan Kauffman (Larry Gates), in the parking lot. He mentioned that he too had seen many perplexing cases of people claiming that loved ones had somehow changed.
Before they could eat, Miles and Becky were called to the house of Jack and Teddy Belicec (King Donovan and Carolyn Jones). They had found an inert, featureless humanoid creature in their poolroom. Teddy was disturbed by it, and the creature seemed to be taking on Jack's features. It even bled from a hand as Jack did when he cut it on a piece of glass. Miles took Becky home to her father's house. Her father (Kenneth Patterson) seemed normal but Miles was disturbed by something. Returning to the Driscoll house later that night, he broke into the basement and found another humanoid transforming itself into Becky. He snuck upstairs and rescued Becky.
Miles and Jack called Dan Kauffman to see the bodies at the Belicecs' and Driscolls'. Both were missing. Dan suggested that they found a real dead human in Jack's poolroom and that its cause of death had been too small for Miles to notice in his examination. He also suggested that Miles saw Becky's double because he had been so unsettled by the mysterious body at the Belicecs'. Becky's father had called the police when he heard Dan, Jack and Miles in his basement. When Police Chief Grivett (Ralph Dumke) arrived, he informed them that a burning body matching the description of what the Belicecs found had been discovered burning outside of town.
In town the next day, Miles encountered Wilma who told him she felt better about Ira and didn't need to see Dan. Based on Miles's demeanor she realized he knew something, and told Becky's father, who was hiding in her antique store. At his office, Miles saw Jimmy smiling next to his mother in the waiting room, apparently unconcerned about her anymore. That night, Miles, Becky and the Belicecs planned to barbeque. But Miles found enormous seed pods in his greenhouse. The pods opened up and inert bodies fell out. They quickly began to take the form of Miles and his guests. Miles tried to call the FBI in Los Angeles, Sacramento and Washington D.C. but was told by the operator that the lines are dead. Miles destroyed the creatures, then he and Becky and the Belicecs split up, hoping to get out of town. Miles and Becky stopped for gas. When Miles went to a phone booth to try to reach the FBI again, the gas station attendant placed two pods in the trunk of his car. Miles realized this and destroyed the pods later. He drove to Sally's house. Sneaking up to a window, he saw that she too had been transformed into a pod person and coolly planned to place a seed pod in the crib of her newborn. Miles was discovered by another police officer. Miles and Becky escaped, pursued by the police and other pod people.
Miles and Becky hid out in Miles's office. Realizing that the pods were most effective at replacing people when they were asleep, they took amphetamines to stay awake. The next morning, they saw police officers detain people just arriving to town, and watched as transformed citizens accepted pods to take to their relatives in nearby cities. Jack, Dan and Chief Grivett arrived. Miles and Becky were horrified to learn they'd all been transformed. Jack and Dan explained that the pods had arrived from outer space and that the transformation was painless. Soon everyone would be reborn into a better way of life, evolved beyond human emotions like hate and love. Jack and Dan brought pods into Miles's waiting room and locked Miles and Becky in the office. Miles filled three syringes with a sedative, then created a diversion that brought Dan and Jack back into the office. Miles struggled with them but drugged them, with Becky taking care of Grivett.
Hoping to pretend to have been transformed by appearing emotionless, Becky and Miles made their way out of the office and into the street. But Becky saw a truck nearly hit a dog and called out in fear. Alerted, the pod people chased Becky and Miles into the hills around Santa Mira. They hid in an abandoned mine. Miles left Becky to try to find help. When he returned, he found Becky asleep. He tried to carry her to safety but learned when he kissed her that she had been transformed too. With other pod people in pursuit, Miles ran to the highway. He pleaded with motorists to stop but they considered him crazy. He saw a truck full of pods headed to Los Angeles. Miles wandered the highway, telling people that "They're already here! You're next!"
Drs. Hill and Basset consider Miles insane and plan his treatment. Then an ambulance brings in a truck driver who had been in an accident. His truck was full of unusual pods, and had been on the road from Santa Mira. Realizing Miles is telling the truth, Dr. Hill immediately calls the police and the FBI.