A photographer named Jerry Manley arrives in Venezuela to be part of an expedition party led by Doctor James Atherton (Julian Sands). Jerry is instructed to take photographs of the animals and environments. The party travels into the rainforest by helicopter and by mule, eventually arriving at the floor of a giant sinkhole. The environment of the sinkhole has been undisturbed for millions of years and Atherton, an arachnologist, is eager to find new species of spiders.
Eventually, the group come across a series of strange webs, and several unknown spiders. Atherton uses smoke collect insect species. One giant specimen that appears to be dead shocks Jerry when it leaps onto his camera. Atherton chastises Jerry for killing it, but they still have some other specimens of the new species to take back. Unseen by the men, a larger spider, the local alpha male, hides on their gear.
Back near their base camp, Atherton examines the specimens, noting that they seem to be 'drones,' as no sexual organs can be found on them, leading him to believe the spiders they've found are part of a 'hive,' with a leader. During this time, Jerry goes to rest, still suffering from a cold he had before he arrived. During his rest, the alpha male ends up biting him and Jerry dies.
When Atherton and his men find out, they assume he must have succumbed to his cold, and a crude wooden casket is constructed to send Jerry back to his home in Canaima in northern California. Unseen by the men, the alpha male stows away in the box.
Once the box arrives in Canaima, the coroners find Jerry's body appears to have shriveled up. The coroner assumes that the remote Venezuelan people lacked the proper equipment and technique to embalm Jerry's body properly. He places a call to the funeral home requesting they speak to Jerry's family and have a closed casket. Meanwhile, the alpha male, having drained Jerry's body during transport, sneaks outside where it is quickly picked up by a crow. After a few moments, the spider bites the crow in midair and both plummet to the ground near an old barn near a farm house.
The house just happens to be the new home of transposed San Franciscan residents, the Jennings. While moving things into the home, Ross Jennings (Jeff Daniels) is asked by his son Tommy to kill a spider. Ross' arachnophobia keeps him from doing so and his wife Molly ends up carrying off the spider. At their daughter Shelley's insistence, they take it to the barn... where it promptly meets and mates with the Venezuelan alpha.
Ross has moved his family from San Francisco, when it was announced that the town's physician Sam Metcalf (Henry Jones) was planning to retire. However, Ross' plans come to a screeching halt when the stubborn Metcalf tells Ross he has reconsidered. Without a secondary job to fall back on, Ross gets some consolation when his nearby neighbor Margaret Collins (Mary Carver) welcomes him, and requests he examine her. After finding her in good health, Ross has her stop taking blood pressure medication that Metcalf prescribed her claiming it's unnecessary.
Meanwhile, trying to find something to do, Molly wanders around looking for things to take pictures of with her camera. Her search leads her to the barn, where she finds a number of unusually large and elaborate webs. She attempts to show them to Ross, who has to fight his phobia just to take a look.
Some time afterward, Margaret hosts a party for the Jennings, and a number of the townspeople get to meet them. The party does get a little off-kilter when Jerry's mother, Henrietta Manley (Lois De Banzie) has too much to drink, wailing about her son who passed away a few months prior.
The next day, Molly calls Margaret to thank her for the party, but gets no answer. Since she lives next door, Ross goes over to check on her, only to find her collapsed on the floor. Dr Metcalf proposes that it was a heart attack, but Ross suspects it could be something else, given that the body was contorted as if she suffered a seizure. When Ross also argues with Metcalf about taking Margaret off the medication he prescribed her, Metcalf accuses Ross, saying his actions could have been the cause of Margaret's death. Ross wishes to perform an an autopsy, but is denied by Metcalf here too.
In the wake of Margaret's death, Ross is unsure what to do, when he is asked by the local school's coach to perform physicals on the school football team. Afterward, Ross watches the team practice for a game, when one of the students suddenly freezes mid-play and is simultaneously hit by three of his teammates. Unseen by the others, a spider had crawled into his helmet, and quickly scurried away when one of the teammates removed it from the collapsed player. The incident soon causes Ross to gain the unfriendly moniker of "Dr Death" by several of the townspeople.
Ross attempts to focus on other things, and tries to finish a wine cellar in the basement, only to find that the beams are rotted. Suspecting termites, they call an exterminator named Delbert McClintock (John Goodman). After looking over the basement, he confirms that it's just the fact that they have "bad wood" in their house, and that they should replace it.
Dr Metcalf is still of the persuasion that Ross is trouble, but is injured when a spider crawls into his slipper and bites his toe. In his final moments, Metcalf has his wife call Ross, but the old man dies before Ross can get to him. It is thought that since Metcalf was exercising moments before his death, that he'd overexerted himself, but Ross and the coroner note a bite mark on Metcalf's big toe, along with his wife telling that her husband claimed he had been bitten by something. Ross then requests the coroner run a toxicology report on Metcalf to properly determine cause of death.
Ross takes on the role of town physician and soon has a full patient load. The coroner soon after calls with the results of Metcalf's findings, noting a small amount of an unidentified poison was found in his bloodstream. Ross then requests that the football player and Margaret's bodies be exhumed to be checked as well, and the coroner complies.
Returning home, Ross finds his daughter going to spend the evening at a friend's home. However, Ross warns the girls to run if they see any spiders, prompting them to giggle at his "silliness."
Later that evening at the Briggs' place (where Ross' daughter is staying), the eldest daughter encounters a spider in the shower, and the father is almost bitten by one. They then after call Delbert out to check the home, but he finds nothing inside. Out on the porch, he sees a spider, and attempts to spray it with one of his special chemical treatments but it has little effect. Frustrated, Delbert simply steps on it.
Meanwhile, given that Ross suspects spiders to be the culprit behind these deaths, he searches for an authority on them, and finds Dr Atherton. Though hoping Atherton will come himself to help, the Doctor claims he's too busy, and sends an assistant named Chris Collins (Brian McNamara) in his place. Chris examines the exhumed corpses and on each one a small bite mark is found, proving Ross' theory.
Eventually, Chris finds the situation dire enough to call in Atherton, who arrives just as the men have found a live specimen. Much like the spiders in Venezuela, the Canaima spiders have no sexual organs, but do have several poison pouches. Testing it on a lab mouse, it dies in a matter of seconds from a very small dosage. It is soon surmised that one of the spiders from Venezuela has mated with the local spiders, and has started its own colony in the town. However, unlike the confined sinkhole in Venezuela where the spiders originated, the open area of Canaima presents no natural features to keep them contained.
They then attempt to get hold of the coroner, but find his phone off the hook. Going to his house, they find that he and his wife have died due to spider bites -- one had found its way into their bowl of popcorn and attacked them while they watched TV.
After the incident, the search is on to locate the nest. Using a map, the group finds out that the attacks have happened in a radiating pattern. At the center of the pattern is Ross' house. As Delbert rushes them to Ross' house, Chris tells them that the alpha male & female will be guarding an egg sac in a place that's warm and devoid of even their drones. Ross immediately thinks of his barn but Delbert counters, saying that the barn would be too cold and drafty. Ross realizes with horror that the spiders have settled into his home.
Atherton also notes Molly's strange webbing photos in Ross' office and has the Sheriff take him to the family's barn. In the barn he finds the webs, along with a number of dead small animals. Atherton attempts to lure out and capture the alpha male, but instead it lunges out and kills him.
Ross and the others have gone to his house where they attempt to get his family out. Sending Delbert to the barn, Ross and Chris go into his house, only to find a number of spiders coming out of the woodwork, to attack them. The family manages to get out, all except Ross, who ends up plummeting over the stairs, and through the rotted wood of the first floor into the cellar.
It is here that he finds the nest with its egg sac. The queen attempts to kill Ross, but he ends up flipping it into the electrical box, where it dies. However, the alpha has appeared, and attempts to kill Ross. The spider even survives being burned, and takes a flying leap at Ross, who impales it with a shot from a nail gun, sending the flaming spider into the nest, destroying it and its offspring. As he lays amid the smoldering wreckage of the basement, Delbert suddenly appears and drags him out.
In the end, we see Ross and his family having returned to San Francisco, and willing to return to the rat race of humanity, where they are sure nothing as crazy as their country adventure will happen... that is, until a few earthquake tremors rattle their apartment.