Captain Thorne Sherman (James Best) and first mate Rook Griswold ("Judge" Henry Dupree) deliver supplies by boat to a group on a remote island. The group, consisting of scientist Marlowe Cragis (Baruch Lumet), his research assistant Radford Baines (Gordon McLendon), the scientist's daughter Ann (Ingrid Goude), her former fiancée Jerry Farrel (Ken Curtis), and a servant Mario (Alfred DeSoto), welcome the captain and his first mate. Before the two visitors can get too comfortable though the islanders, to their surprise, begin to insist that the ship leave immediately and take Anna with them, even though a hurricane is fast approaching the island. Thorne however insists that the storm will be too severe for them to leave that night and so instead goes with the researchers to their compound, while Griswold stays with the boat, saying that he will come ashore later.
Over cocktails at the compound, Thorne soon becomes aware of a menace threatening all their lives and the reason for why the Doctor and company were so eager for the ship to leave quickly: Marlowe Cragis as it turns out has been performing well-meaning genetic research and has been using shrews as test animals due to their short life spans allowing him to track his research's progress over multiple generations. The Doctor's purpose in these experiments is to isolate and manipulate the genes responsible for growth and metabolism in order to eventually shrink humans to half their size so as to reduce world hunger because (he reasons) being smaller, the modified humans will consume less food in a world with a limited food supply. Unfortunately, the Doctor's experiments have instead created a batch of mutant giant shrews that have escaped due to Farrel's drunken negligence and which are now reproducing in the wild, growing larger and more voracious by the day. Due to this, the group must now barricade themselves inside their compound every evening before the sun sets due to the creature's nocturnal feeding habits, with the hope being that the shrews will inevitably kill and cannibalize each other once they have eaten every other living animal on the island.
Gradually as they talk Thorne and Ann become more and more attracted to each other, causing Jerry to become jealous. Meanwhile, the giant shrews having run out of smaller animals to hunt and devour become ravenous and begin to venture out during the day in a desperate attempt to find food. As a result when Griswold comes ashore, the mutants attack and kill him. Shortly afterward the storm makes landfall and the shrews dig through the floor of the compound's barn and begin attacking the livestock. Hearing the sound and mistaking it for Rook, Thorne nearly opens the door to let him in but is stopped from doing so by Jerry and Marlowe who make him realize the truth of the matter. Marlowe then attempts to reassure Thorne that they are safe in the building from the shrews but his attempts quickly falter when Thorne points out a fact the Doctor has overlooked. As Thorne explains, while the main building's floor is indeed too hard for the shrews to dig through, the walls of the building are adobe and at the current rate, the storm will soon turn it to soft mud making the Doctor's plan to simply wait out the shrews impossible. Recognizing the truth of his statement the group makes a plan to leave the moment the storm is over. Later that night though one of the mutant shrews takes advantage of a broken window and makes its way into the basement. Mario and Thorne hearing the noise and realizing one of the creatures must have forced its way inside follow it downstairs. Mario discovers the mutant and shoots at it, but not before it bites him. The giant shrew is subsequently finished off by Thorne who then attempts to treat Mario's wound only for him to die regardless. Radford later discovers Mario's death was due to a highly toxic venom in the dead shrew's saliva, the result of the creatures adapting to the poisoned bait the researchers had placed in the wild in a previous attempt to kill them off. As day breaks and the storm fades, Thorne and Jerry attempt to scout the path out of the compound so the whole group of survivors can hopefully make a break for the boat. During this mission, the two of them discover Rook has been eaten by the creatures and Jerry's jealousy over Anna's attraction to Thorne leads him to try and shoot his rival only for Thorne to disarm Jerry. The shrews then suddenly attack the two and Thorne and Jerry race back to the compound. Jerry reaches it first and tries to leave Thorne locked outside to die but Thorne just barely manages to scale the compound's fence in time. Enraged by the multiple attempts to kill him Thorne beats Jerry senseless and nearly throws him to the shrews but thinks better of it and spares him instead. After dragging Jerry back into the main building the survivors regroup to try and come up with another plan. Before they can do so though, another mutant shrew is able to get in and bites Radford before they can kill it. As he dies, Radford, ever the dutiful researcher, records the symptoms of the venom on his typewriter, right up to the moment of his death.
As more and more of the giant shrews begin to chew through the now soft adobe walls, Thorne hits upon the idea to fashion impromptu armor by lashing together empty 50-gallon chemical drums and then duckwalking to the beach. Due to his claustrophobia though, Jerry refuses to get into the makeshift armor and remains behind, isolating himself on the roof and watching the mutants chase after the lashed-together drums. When the coast seems clear Jerry attempts to flee but is cut off and killed by another group of shrews. Thorne, Ann, and Marlowe meanwhile manage to reach the shoreline and after ditching the armor they swim out to the boat. Safely aboard and confident that the giant shrews will eventually die out from consuming one another, Thorne and Ann share a long kiss.
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