A man with a strangely misshapen face wanders out of the desert near a small town and falls to the ground dead. The county sheriff (Nestor Paiva) tentatively identifies the dead man as Eric Jacobs, a laboratory assistant to Professor Deemer (Leo G. Carroll), a research scientist living a few miles out in the desert. But there's something strange about Jacobs; his facial features and bodily extremities are distorted to a point where he's barely recognizable. The sheriff calls in Dr. Matt Hastings (John Agar), the local physician, who makes a diagnosis of acromegalia, a glandular disorder that affects the body's growth. He also tells the sheriff that it can't possibly be acromegalia, because symptoms as pronounced as those he sees in this case take years to develop, and the man was in perfect health just three months earlier. Hastings refuses to believe the professor's account of Jacobs' rapid deterioration, but the sheriff takes the word of the scientist. Back in his laboratory, Deemer continues his work, going over tests of a chemical on various animals, all of which are jumbo-sized, including guinea pigs the size of rabbits, baby mice the size of full-grown rats, and a tarantula three feet long. Suddenly, the professor is attacked by his assistant (Eddie Parker), whose face and hands are distorted in the same manner as Jacobs, and who injects the helpless scientist with the experimental chemical before collapsing dead. A fire starts during the attack and in the confusion, the tarantula's glass cage is broken and it escapes the burning laboratory, wandering out into the desert. Weeks go by, and a new assistant, Stephanie "Steve" Clayton (Mara Corday), arrives to begin work for the professor. When Hastings gives her a ride to Deemer's home, the scientist explains to the doctor that he's been working on a radioactive nutrient, that, if perfected, could feed the entire world's population. He also says that Eric Jacobs made the mistake of testing the chemical on himself and it caused the disease that killed him. Hastings and Steve begin a romance, unaware that wandering around the desert is the tarantula from Deemer's laboratory, now grown to the size of an automobile and getting bigger with each passing day. Soon livestock and then people begin disappearing, and the sheriff is at a loss to explain any of it, or the one clue left behind in each case: large pools of what seems to be some kind of venom next to the stripped skeletons of the victims. Hastings takes some of the material in for a test; meanwhile, Steve notices that Deemer is going through some bizarre changes. His mood has darkened and his features now appear to be changing, as the acromegalia, caused by the injection, manifests itself. Hastings learns that one of the professor's test animals was a tarantula, which was presumed destroyed. When he learns that the pools near the deaths are composed of spider venom -- equivalent to what it would take many thousands of spiders to generate -- he's certain that the tarantula from the laboratory survived. By this time, the title creature is bigger than a house and ravaging the countryside, killing everything in its path and knocking down power lines and telephone poles as it moves. Hastings arrives just in time to rescue Steve from the attacking creature, which destroys Deemer's house and kills the professor. The sheriff and the highway patrol are unable to slow the creature, now the size of a mountain and moving at 45 miles an hour, even with automatic rifle fire, as it follows the road through the desert toward the town. Even an attempt to blow it up with dynamite fails when the monster walking right through the blast. Finally, the creature is poised to attack the town, when jets scrambled from a nearby Air Force base (led by a young Clint Eastwood, barely recognizable behind an oxygen mask) swoop in. When rockets fail to divert the monster from its path, the jets roar in for a second pass and drop enough napalm to incinerate the creature.