A meteorite housing a malevolent, sentient extraterrestrial parasite crashes into the town of Wheelsy, South Carolina. While frolicking in the woods with Brenda, local car dealer Grant Grant finds the parasite and is infected by it. The parasite takes over his body and absorbs his consciousness and memories. With the alien now in control of his body, 'Grant' begins to slowly change into a tentacled slug-like monster.
Many pets soon disappear, but Grant is not suspected. However, his wife Starla begins to question his health; he explains the initial changes in his appearance as an allergic reaction to a bee sting, saying that a doctor has already given him something for it, but Starla soon learns this is a lie. Starla contacts the police chief Bill Pardy – her childhood crush – who attempts to reassure and comfort her while not acting on his feelings. Grant infects the lonely and neglected Brenda with hundreds of his offspring. He hides her in an isolated barn where she becomes massively obese to the point of inflating to the size of a wrecking ball as baby alien slugs grow inside her. Bill leads a small group of officers on a hunt for Grant; they find Brenda in time to see her explode, releasing hundreds of the alien slugs. Most of Bill's group are infected by the slugs and become Grant's puppets, speaking as if they were Grant and obsessed with bringing Starla home and holding her to her wedding vows.
Everyone in town is quickly eaten or absorbed into Grant's hive mind except Starla, Bill, mayor Jack MacReady, and a teenage girl, Kylie, who escaped a partial bonding in which she saw the slug's memories; it moves from planet to planet, eating or absorbing all life it finds there. The parasite's consciousness, however, is influenced by the real Grant's memories and his love for his wife, Starla.
The survivors try to escape detection and kill Grant. The townspeople attack their vehicle, capturing Starla and Jack. Bill and Kylie track Starla to her home, and find that the infected are melding into one giant creature. They must risk their lives to stop the infestation from spreading any further. Jack awakens in the house's basement, where several of the infected are eating; he tries to escape but becomes infected as well. Starla charms the monster by calling him "Grant" and telling him they can be together, but as they get close to each other, she pulls a mirror from her underwear and stabs him in the chest with the pointed handle. He slaps her with a tentacle and knocks her across the room.
Bill arrives; Jack begs to be killed, and Bill shoots him in the head. He tries to kill the monster with a grenade, but another tentacle knocks the grenade into the pool, where it detonates. The monster sends two tentacles to stab Bill and infect him; one is lodged in his abdomen, but Bill attaches the other to a small propane tank, filling Grant with gas, and Starla shoots the monster, causing it to explode, whereupon all the infected die. The three survivors walk away to find a hospital for Bill.
In a post-credits scene, a cat approaches to feed off Grant's remains and is infected.
- Nathan Fillion as William "Bill" Pardy
- Elizabeth Banks as Starla Grant
- Gregg Henry as Mayor Jackson "Jack" MacReady
- Michael Rooker as Grantham "Grant" Grant
- Tania Saulnier as Kylie Strutemyer
- Matreya Fedor as Emily Strutemyer
- Don Thompson as Walter "Wally" Whale
- Brenda James as Brendadetta "Brenda" Gutierrez
- Jenna Fischer as Shelby Cunningham
- Jennifer Copping as Margaret Hooper
- Haig Sutherland as Trevor Carpenter
- Amber Lee Bartlett as Jenna Strutemyer
Slither received generally positive reviews. The film-review aggregator Rotten Tomatoes reports 86% of critics gave a favorable review; the consensus states: "A slimy, rotten B movie homage oozing with affection for low-budget horror films, Slither is a tale of creepy crawly little beasts that invade Smalltown, USA. Equally creepy and funny, critics say it's one of the most enjoyable of its type in years -- if you've got the stomach for this sort of thing. Slither is a wicked good time: it'll make you squirm -- when you're not busting a gut laughing." The movie was also featured in the April 14, 2006 issue of Entertainment Weekly as #1 on "The Must List"; "Ten Things We Love This Week". Slither picked up the 2006 Fangoria "Chainsaw Award" for the Highest Body Count, and garnered nominations in the categories of Relationship From Hell, Dude You Don't Wanna Mess With, and Looks That Kill. Additionally, the horror magazine Rue Morgue named Slither the “Best Feature Film of the Year”. Among the critics who did not like the film, Roger Ebert and Richard Roeper gave Slither a "two thumbs down" rating on their television show, with Roeper saying he was "all zombied out" after reviewing a wave of zombie-themed films from the year before. Guest critic Michael Phillips named Slither his DVD pick of the week on the television show Ebert & Roeper. Slither was listed as one of the “Top 25 DVDs of the Year” by Peter Travers in Rolling Stone magazine.