When a mysteriously deformed man, Eric Jacobs (Eddie Parker in an uncredited role), is found dead in the desert, Dr. Matt Hastings (John Agar), a family doctor in the tiny neighboring town of Desert Rock, is called in to examine the body. Jacobs, a research scientist, worked with Prof. Gerald Deemer (Leo G. Carroll), a reclusive scientist who's conducting mysterious experiments at an out of the way mansion near the town.
Dr. Matt is baffled by the cause of Eric's death. His distorted features suggest acromegaly, a disorder of the pituitary gland, but since Eric was fine just days earlier, Matt can't understand why he would deteriorate so quickly. When Professor Deemer insists that it is acromegaly and refuses to authorize an autopsy, Matt is both annoyed and confused. The local Sheriff, Jack Andrews (Nestor Paiva) takes the Professor's side. Later, Deemer returns to his lab, where it's revealed he's working on creating a food nutrient to feed the world's increasing population.
He has injected the nutrient into lab animals, which have grown at astonishing rates. A caged tarantula is several times normal size. Suddenly, Deemer's other assistant, Paul Lund (Eddie Parker in an uncredited role) stumbles into the lab, his face as hideously distorted as Jacobs'. Delirious, Paul attacks Deemer and busts up the lab, setting the tarantula loose. He also injects the unconscious Deemer with the nutrient, then dies as the lab begins to burn. Deemer awakes in time to put out the fire, then buries Paul's body without notifying authorities. The following day, beautiful Dr Stephanie "Steve" Clayton (Mara Corday) arrives in Desert Rock, having been hired by the late Jacobs. Matt gives her a ride to Deemer's, informing her of Jacobs' death.
When they reach Deemer's house, the Professor pretends the damaged lab was an accident. Deemer explains how he is making the nutrient using the power of the atom to bind the solution. Stephanie becomes an able assistant to Deemer, helping him with his experiments. She also gets to know Matt, who shows her the town and desert scenery. Meanwhile, something odd is going on in the desert. Something unknown is devouring the horses, their skeletal remains found by local ranchers. Two human beings appear to have been devoured after an apparent car accident. Matt notices huge pools of a mysterious substance near the accident.
After lab analysis, he discovers that it's insect venom ű but in an enormous quantity. At the lab, Stephanie becomes concerned about Deemer, whose face is gradually becoming distorted, much like Jacobs and Paul. When Deemer finally confesses to Matt and Stephanie that Paul went on a rampage and released the tarantula, Matt becomes suspicious, making a connection to the recent phenomena. Meanwhile, the tarantula continues its rampage, killing two old prospectors in the desert. While studying in her bedroom that night, Stephanie doesn't see that the tarantula is approaching in the distance, visible from her bedroom window.
Once the tarantula begins wrecking the house, a horrified Stephanie tries to save Deemer, who's convalescing in his room, his face now completely distorted. Unfortunately, the tarantula kills Deemer before Stephanie can save him. Matt drives up to the house as it collapses, but Stephanie gets out alive, rushing to Matt's car. They drive off into the desert, notifying the State Police and Sheriff, who gives orders to evacuate the town. Efforts to kill the approaching tarantula with machine guns fail, and the monster kills two cops in the bargain. Another effort to kill the monster with dynamite also fails. With the tarantula headed for town, fighter planes approach, with Clint Eastwood in an undredited minor role as the jet squadron league.
They drop bombs on the monster as it reaches Desert Rock. When traditional bombs fail, the planes drop napalm, setting the tarantula on fire as a relieved Matt, Stephanie and various officials look on..