An alien entity, resembling a spore or fungus, attaches itself to the space shuttle Patriot as it crashes back to Earth, dispersing contaminated debris across locations from Texas to Washington, D.C. Intrigued by the wreckage, onlookers begin to touch, steal, and even sell the remnants online, echoing the aftermath of the Columbia disaster. This reckless curiosity leads to a rampant infection among many people, stripping them of their emotions while they enter REM sleep.
Among the first affected is Tucker, a CDC director who is tasked with investigating the crash. Overwhelmed by the alien invasion, Tucker leverages the CDC to further propagate the disease, camouflaging the spores as flu shots. This deception incites a widespread panic regarding a fabricated "flu bug," causing a surge of desperate individuals to rush for the "inoculations," ultimately transforming into lifeless pod people when they succumb to sleep that night.
Meanwhile, Carol Bennell, a psychiatrist and Tucker's ex-wife, senses something is fundamentally wrong. After uncovering several patients claiming their loved ones have become "imposters," she partners with her love interest, Ben Driscoll, who is also a doctor, to unveil the disturbing truth behind the infection.
With assistance from Ben's friend, Galeano, a biologist, they delve into the nature of the spores, discovering that it overrides the brain during REM sleep. They uncover a critical detail: individuals afflicted by previous diseases affecting the brain, like syphilis or ADEM, possess immunity to the spore due to their conditions preventing the spore from anchoring onto their brain matter. Impressively, Carol's son, Oliver, is also immune after suffering from scarlet fever-type symptoms as a child. They identify Wendy Lenk, one of Carol's patients, as another immune individual who narrowly escaped to her sister’s residence.
During one harrowing day, Carol notices numerous distressed individuals, including a homeless man exhibiting violent convulsions. Upon reaching her office, reminiscing about Wendy's warning regarding her husband, she frantically searches online but is soon targeted by her infected secretary, who contaminates her favorite tea to spread the disease. Just as she is about to sip the tainted beverage, a timely phone call from Ben interrupts her.
As Carol gathers with Ben, Ludmilla, and others, she witnesses a person named Yorish undergo transformation into an infected being. Struggling to capture evidence, Carol partially rouses him from REM sleep, inadvertently causing him to suffer a cardiac arrest. Alarmed, she ventures to retrieve Oliver from Tucker. When she arrives at his house, an alarming confrontation ensues, with Tucker and his colleagues trying to capture her, leading to an infection attempt as he spits on her. However, she escapes and finds refuge at a safe location.
Meanwhile, food supplies are dwindling at a base outside Baltimore, where Stephan and Jill have successfully arrived, joining several Nobel Prize winners in their mission to develop an antidote for the alien virus. Carol and Ben split up to locate Oliver, who thankfully manages to text Carol with his position. However, a chase ensues with the infected, and Carol cleverly feigns illness when confronted by Tucker's neighbor's child, Gene, who unwittingly takes her back to Tucker's family home.
In a tense moment, Carol cleverly disguises her intent, intending to reunite with Oliver, but they’re interrupted by Gene. Maneuvering through the chaos of normal people pretending to be infected, Carol resorts to taking prescription amphetamines to fight sleep. A chance encounter with Ben reveals his infection, leading Carol to use a weapon she previously acquired to fight back against the infected individuals, managing to incapacitate several victims, but shoots Ben, who is now a threat.
Eventually, a helicopter arrives to rescue Carol and Ben from the rooftop, whisking them away to the operational base where scientists work alongside Galeano to create an airborne vaccine utilizing Oliver’s blood. Since the spore commandeers the brain during REM sleep, those cured experience a disorienting sensation, akin to emerging from a dreamless slumber.
In the film's poignant conclusion, Carol and Ben reflect on the chilling emotionless state of the pod people as they peruse the newspaper, confronted by headlines of "business as usual," reiterating the harsh reality of tragedies, conflicts, and violence still rampant in their world.
