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In 1976, a plague kills almost all people on the planet. After their deaths, those who died rise from the dead and become vampires—they’re sensitive to sunlight, garlic and mirrors; they don’t sleep during the day; and they’re impervious to bullets. A man named Robert Neville has survived by converting his house into a fortress every night (he goes out in daylight) so he can impale sleeping vampires with wooden stakes before sunrise. Every night, he hears his neighbor shouting for him to come out of his house because it’s safe now that there are no humans around.

Neville has several close encounters with vampires. One night, his watch stops working and he drives home after sunset to fight off some vampires. He barely makes it back alive. Afterwards, Neville drinks heavily and sinks into depression. We learn that this is because of the death of his wife Virginia in 1975 when a plague swept across the world; she was burned in a pit along with many other victims of the plague but came back as a vampire—Neville had to kill her again. We also find out about Kathy, Neville’s daughter who died from the same disease; he buried her body instead of burning it and then she rose from her grave as well!

Neville is trying to stave off his depression and loneliness by learning about the vampires. He kidnaps sleeping vampires from their hiding places, and takes them back to his house where he waits for them to wake up. Neville then dangles crosses in front of their faces—he finds that some, but not all, of the vampires are repulsed by the sight of a cross. Neville also learns that it’s possible to kill vampires by piercing their bodies anywhere—it doesn’t have to be the heart contrary to folklore. He tries injecting garlic into vampire’s blood stream but gets no reaction from them so he isolates a germ which is responsible for vampirism in humans who still have control over themselves but cause corpses raised from graves become wild and feral creatures called true undead.

One day, Neville notices that there’s a dog outside his house. The dog appears to be infected with the vampire germ and seems scared of him. Neville tries to befriend it by feeding it hamburger meat but he can’t get the dog to enter his house. Eventually, the dog becomes so sick that it eventually dies from the infection.

Neville realizes that he can’t use alcohol to cope with the death of his dog, so he throws himself into research. He hypothesizes that some vampires are afraid of crosses because they remind them of their former Christian lives. However, Jewish or atheist vampires may not be afraid of the cross at all. The novel then jumps ahead two years: it’s 1978 and Neville is more comfortable in his new life as a vampire hunter. The hunt for Ben Cortman is the best part of Neville’s day—indeed, it’s better than hunting other vampires. One day, Neville sees Ruth running through town. She initially refuses to stop and talk to him but eventually agrees to go back home with him. At home, she tells Neville about her husband who died just a week ago.

Neville tells Ruth about the vampires he’s been fighting, and how they’re immune to bullets because their bodies create a glue. He also explains that he’s immune to this germ because he was bitten by a vampire bat in Panama. Neville is able to kill them while they sleep, but feels guilty for doing so. Later on that night, it’s implied that Neville and Ruth have sex together.

Neville insists on testing Ruth’s blood to see if she has the vampire germ. He does so and immediately sees that she is infected with the germ. When he looks into his microscope, Ruth knocks him out and leaves a note explaining that she is a member of a group of living vampires who are still able to resist the effects of the vampire germ by taking pills for it. Neville killed her husband while he was sleeping, which made her feel like she had no other choice but to leave Neville after falling in love with him.