Robert Morgan (Vincent Price) is the last man on earth, as far as he can tell. A plague killed everyone else on the planet several years ago. He was immune to it, and can only guess why. Vampires that were formerly human attack Morgan's home every night.
Morgan's days are spent shoring up his home against the vampire hordes, picking up supplies in the abandoned city, and eliminating his enemies by searching out and destroying the bloodsuckers while they sleep. He maintains mirrors and garlic strands around his house and fashions stakes on his lathe to use on the walking dead. He also conducts experiments on the bacteria that caused this plague in an effort to find a cure.
He remembers the early days of the plague, when his former friend and lab partner, Ben Cortman (Giacomo Rossi Stuart) tried to warn Morgan of what was to come. Morgan dismissed his fears and continued life as usual.
The vampires outside Morgan's home are led by Ben Cortman, who has made it his personal mission to kill Morgan. "Morgan, come out!" is the nightly chant that torments him.
His solitary existence is painful. He gets on the radio every day, calling out on different frequencies, trying to find another human still alive. In his tortured dreams, he remembers when his wife returned from the dead to seek his blood, after she succumbed to the plague.
One day, to his amazement, he finds a dog. He is so excited to have a companion that he overlooks several signs that all is not right with the animal. Eventually, he realizes that the dog is also infected and that he must kill it.
While burying the dog, Morgan encounters Ruth Collins (Franca Bettoia), a woman walking through the park in the sunshine! Even though he's suspicious of her story of how she survived, he takes her home with him. She reacts violently to a garland of garlic cloves he brings out, but she claims that she's always had a weak stomach.
Ruth also warns Morgan that her people are coming for him because, in his zeal to kill vampires, he has been killing people like her who have the disease under control. Morgan injects Ruth with some of his own blood and cures her of the disease completely. His blood is the permanent cure that Ruth and others like her have been searching to find.
At this moment, however, the soldiers come for him. Before Ruth can tell them that Morgan has found a cure, he is surrounded and shot. As he stumbles to his death, he tells the crowds that they are freaks and that he is "the last man on earth"!