A group of scientists, led by entomologist Dr. James Atherton (Julian Sands), head to the Amazon with the hope of discovering new species of insects. The scientists identify a new species of spider, which is pretending to be dead and carries a type of venom that causes near-instantaneous death to its victims. The spider is captured and chloroformed for research. They learn that the spider is a soldier. A nature photographer Jerry Manley (Mark L. Taylor) takes a rest under the tree where the spider was found, and the 'general' (leader) spider jumps into his backpack, later sneaking into his sleeping bag and killing him with a bite to his hand. The remainder of the scientists take his body back to the US, in a wooden box, with the original spider from Venezuela inside, blaming Jerry's death on fever.
Jerry's body arrives at the morgue in his home town, Canaima, and the mortician (Roy Brocksmith) doesn't notice the general spider inside the coffin when he opens it. He is disgusted to find Jerry's body completly drained of blood. As the mortician is speaking on the phone with Jerry's family about funeral arrangements , the general heads outside. It, comically, eventually makes its way to the barn of the Jennings family. Ross Jennings (Jeff Daniels) is a family physician, who had moved to the small town from San Francisco, and faces a lack of patients due to elderly rival Sam Metcalf (Henry Jones), who was supposed to retire and shift his patients to Ross.
The general spider mates with a domestic house spider and makes a nest in Jennings's barn, producing a queen, then mates with the queen and makes a second nest in the family's basement. Hundreds of soldier spiders are born in the barn. Ross, along with his son (Garette Patrick Ratliff), has arachnophobia (fear of spiders), making them targets of ridicule among their family (Harley Jane Kozak and Marlene Katz). His first patient, Margaret Hollins (Mary Carver), dies after being bitten, which the town's residents believe was a heart attack. After a football player (Nathaniel Spitzley) is also killed by a spider, Ross is known to the town as Dr. Death, because each of his patients dies after having seen him. Soon, when Metcalf himself is bitten on the toe and killed by a spider, giving Ross the idea that the town could be infested by deadly arachnids. After Ross perform an autopsy with the town's coroner Milton Briggs (James Handy (who tells the Sheriff, Lloyd, to shut up a lot) on the victims and confirms his suspicion, he, along with Dr. Atherton, his assistant Chris Collins (Brian McNamara), Briggs, Sheriff Lloyd Parsons (Stuart Pankin), and exterminator Delbert Mclintock (John Goodman) investigate and eventually discover that the killer spiders are descendants of the new species Atherton discovered earlier. Dr. Atherton is bitten on the neck and killed by the general after he discovers the primary nests' location and disturbs its web.
After Ross, Chris, and Delbert trace the nests to Jennings' own property, Ross sends Delbert to destroy the first nest at the barn while he and Chris try to help the family escape from their own house, now infested with deadly spider offspring, coming in through all different places in the house. Ross's wife, his children, and Chris make it out through the window, but Ross finds himself trapped until he falls through the basement into the spiders' second nest. After electrocuting the queen, Ross battles the male, attempting to destroy the second egg sac along with burning the spider to death with fire spray. When the spider is about to deliver the killing strike, Ross flings the spider into the fire with a board on his chest.
When the egg sac hatches, the male, on fire, jumps out of the fire still pursuing him. Ross shoots it with a nail gun and the projectile sends the burning spider to the nest's egg sac, effectively destroying the nest with fire and ending the plague. Delbert is able to reach Ross and get him to safety. Having enough of the country along with the near-death experience, the Jennings family immediately move back to San Francisco, appreciating city life once more.