The morning after a severe thunderstorm leaves the town of Bridgton, Maine without electrical power, an unnaturally thick mist gradually envelopes the area. Commercial artist David Drayton, along with his young son Billy and neighbor Brent Norton (whose prized vintage car has been smashed by a fallen tree), go to the local supermarket for groceries, leaving David's wife Stephanie behind at their home. Upon arrival, their suspicions are aroused by the sound of a siren. The mist completely covers the supermarket and conceals strange and hostile creatures. The situation is aggravated by an earthquake, which damages communications and leaves the store without electricity. When a young bagger, Norm, goes outside to fix a clogged vent in the store's generator, he is dragged into the mist by a mass of giant tentacles.
David and assistant manager Ollie Weeks witness Norm's death and try to convince the remaining survivors of what has happened, imploring that no one leave the store. Norton and a small group of people accuse David of lying and go outside for help, only to be killed by unnatural predatory creatures. Ollie is given a revolver by the young Amanda Dumfries. Large "insects" begin crawling over the outside of the store, attracting pterosaur-like creatures, one of which squirms inside through a broken window and is killed with an improvised torch amidst a general panic. Searching for an escape and needing to treat an elderly woman who was injured in the panic, David leads a group of people to retrieve medical supplies from an adjacent pharmacy, where they encounter huge spider-like creatures. Only half the expedition survives the retreat, heavily demoralizing everyone else inside the store. In the wake of mass hysteria among the survivors, religious fanatic Mrs. Carmody gradually convinces them that the current events fulfill a biblical prophecy of the end time, and that human sacrifice is required to save themselves from God's wrath.
Two soldiers from a nearby military base reveal that the mist may be associated with "Project Arrowhead" – in which they were involved – before committing suicide. When David, Billy, Ollie, Amanda and a few other survivors attempt to escape to David's car, they are confronted by Mrs. Carmody, who calls on the crowd to offer Billy and Amanda as sacrifices. Ollie shoots Mrs. Carmody, and her "congregation" dissolves in confusion. En route to the car, Ollie and one other survivor are killed, while another flees back to the store. The rest attempt to reach David's house to determine Stephanie's fate, but the driveway is hopelessly blocked by fallen trees. They drive south through a devastated and mist-shrouded New England, witnessing further signs of catastrophe and more mysterious creatures. While stopped for the night, David searches the radio bands and, through the mist's interference, possibly hears someone say "Hartford", giving him a last shred of hope.
