Photographer Jerry Manley arrives at the Venezuelan base camp of entomologist Dr. James Atherton. Despite Jerry’s complaint of fever, James whisks him by helicopter to a remote giant sinkhole, where Jerry helps James and his assistants set up cones to catch falling butterflies as James pumps smoke into the trees. Several huge spiders also fall, and James captures two in jars, but a third spider slips into Jerry Manley’s backpack. Back in camp, as James studies the spiders, he notes that, like solider ants, they have no reproductive organs. While Jerry rests in his tent, the third spider crawls from his backpack and delivers a fatal bite to his stomach. Thinking Jerry died of fever, James packs his body into a box to be shipped home, but the spider slips inside. When the body arrives in Canaima, California, mortician Irv Kendall is shocked at its desiccated condition, as if something sucked it dry. The spider sneaks out of the box and escapes through a cat door. A crow swoops down and picks it up, but soon plummets lifelessly into the yard of a house where Dr. Ross Jennings, his wife Molly, and children Tommy and Shelley have just arrived from San Francisco, California. Dr. Jennings has chosen to take over as town physician when Dr. Samuel “Sam” Metcalf retires the following week. Tommy Jennings sees the large spider and reports it to his mother, who finds a smaller, harmless spider instead and releases it in the barn out back. The foreign spider joins the domestic spider, and the two mate. When Dr. Jennings visits Sam to discuss taking over his practice, the old physician has second thoughts about retiring. Jennings panics, because he has bought a house and rented an office in Canaima. Retired schoolteacher Margaret Hollins volunteers to be his first patient, and when he gives her a check-up, he discovers that Sam unnecessarily put Margaret on high blood pressure medication. Meanwhile, Molly, an amateur photographer, takes pictures of a large web in the barn. Hoping to cure her husband of his fear of spiders, she takes him to see it, but Ross is terrified by his earliest childhood memory of a spider crawling on him. Just out of sight in the loft, an egg sac pulsates. Later, Margaret throws a lawn party to introduce Dr. Jennings to the townspeople, and Tommy and Shelley make friends with neighbor Bunny Beechwood, whose father, Henry Beechwood, is the high school coach. Other guests include Jerry Manley’s parents, grieving over their son’s death and angry they could not view his body before burial. That evening, a spider gets into Margaret’s house and fatally bites her hand. The next day, Dr. Jennings attempts to convert his basement into a wine cellar, but the wood is rotten. When he fires a nail gun into the ceiling, the nails shoot through the floor boards above. He goes to Margaret’s to thank her for the party, and sees her body through a window. Sam Metcalf declares she had a heart attack and blames Ross for taking her off blood pressure pills. Recognizing signs of convulsion, Ross suggests an autopsy, but Sam refuses, because locals object to having their bodies desecrated. Margaret is buried without being examined. Meanwhile, Molly Jennings hires local exterminator Delbert McClintock to check the house for termites, but he finds only “bad wood.” Henry Beechwood asks Dr. Jennings to give his football players physical examinations. Later, during practice, a spider crawls into a football helmet. After player Todd Miller puts it on, he is bitten while being tackled and dies. His teammates surround him, take off the helmet, and lay it aside. Nobody sees the spider crawling out, but a player steps on it and kills the arachnid without noticing. Though Todd’s death is blamed on the tackle, some wonder if Dr. Jennings is to blame and call him “Dr. Death.” That night, Dr. Sam Metcalf steps off his treadmill before bed, puts his foot into a slipper, and is bitten. His wife, Evelyn, calls Dr. Jennings, but the old doctor is dead by the time he arrives. When County Medical Examiner Milton “Milt” Briggs arrives, Dr. Jennings tells him that Metcalf’s wife saw a spider, then shows him a bite on the old doctor’s toe. Milt argues, however, that spider bites are rarely fatal. He blames the elderly doctor’s death on overexertion on the treadmill. Dr. Jennings demands an autopsy, and the next day, Briggs telephones to say Dr. Metcalf died from a tiny amount of unknown toxin. Over the objection of Sheriff Lloyd Parsons, Dr. Jennings asks Milt to exhume Todd Miller and Margaret Hollins. Dr. Jennings warns his children to watch out for spiders. While playing with Bunny at the Beechwood house, Shelley Jennings is almost bitten by a spider, but Bunny innocently drops a large book on it. Meanwhile, Ross finds a cricket in the house and realizes he has not heard them lately, even though crickets chirping on quiet evenings was one of Canaima’s selling points. Seeing that Dr. James Atherton, one of America’s foremost entomologists, is studying spiders at a California university, he telephones him. Atherton tells him that people frequently report false outbreaks of spider deaths. However, after he hangs up, Dr. Atherton vaguely recalls the name Canaima. Studying his new species of Venezuelan spiders, he asks his assistant, Chris Collins, to investigate. Chris arrives in Canaima just as Dr. Jennings and Milt find spider bites on the exhumed bodies of Todd Miller and Margaret Hollis. The young assistant telephones Dr. Atherton and asks him to come. The next day, as Dr. Jennings, Milt, Sheriff Parsons, and Chris search Margaret’s property, they find a large web filled with fragments of crickets, along with a dead spider. Chris Collins observes that another spider drained it, because spiders are like vampires. Suddenly, a spider menaces them. Dr. Jennings freezes with fear, but makes enough movement to distract the spider, allowing Chris to drop a glass over it. Nearby, as Bunny’s older sister, Becky Beechwood, takes a shower, a spider drops on her from the shower rod, but the rushing water sends it skittering down into the drain. Henry Beechwood telephones Delbert McClintock, who arrives and finds a spider on the front walk. The exterminator’s insecticide has no effect, however, so he squashes the spider with his boot. When Dr. James Atherton arrives in town, Dr. Jennings claims that he and Irv Kendall have already figured out that a spider escaped from his Venezuelan camp in Jerry Manley’s casket. Studying the captured spider, Atherton notes the huge fangs and the lack of sex organs, which is uncharacteristic of spiders, except for the Venezuelan species. He explains that this type of spider has been trapped for millennia in a deep gorge, but now one of them has mated with a local species, and their offspring will spread out. Though these sexless spiders will soon die, a new queen has probably been born, and her offspring will be unstoppable. Her nest must be destroyed. That night, at Irv Kendall’s house, a spider gets into a bowl of popcorn and kills him and his wife. The next day, when Atherton goes to Dr. Jennings’ office with Sheriff Parsons, he sees Molly’s photographs of the huge barn web and demands to go there. Elsewhere, Chris Collins tells Dr. Jennings the queen will be hiding in a dark, musty place, and no other spiders will be around because the queen protects her babies. Plotting a map of where spiders were seen or people were bitten, Chris draws a circle around the Jennings house. Meanwhile, as Atherton investigates the web in the barn, the original Venezuelan spider fatally bites him. Dr. Jennings arrives to evacuate his family, but they are surrounded by hundreds of spiders and must escape through an upstairs window. However, Jennings again freezes at the top of the stairs and tumbles over the railing. He crashes through the rotted ground floor and lands in the cellar. Seeing no spiders, he knows from what Chris Collins said that this must be where the queen is hiding. When it attacks him, he shovels the spider toward a broken fuse box and electrocutes her. Finding a giant egg sac, he douses it with wine. As the original Venezuelan spider drops down on him, he knocks it away, chases it with flames, and sets part of the basement on fire. He momentarily freezes as the spider crawls up his leg, then knocks it away into the fire. As the flaming creature leaps at him again, Ross fires his nail gun and sends the burning spider into the egg sac, setting it afire. Delbert McClintock pulls him to safety. Later, Dr. Jennings and his wife, having returned to San Francisco, drink wine, happy to be home. After their ordeal, they are only mildly disturbed when an earthquake hits.