The book takes place in the then-future of 1976–1979, and opens with the monotony and horror of the daily life of the protagonist, Robert Neville. Neville is apparently the only survivor of an apocalypse caused by a pandemic of a bacterium the symptoms of which are very similar to vampirism. He lives in a house fortified against nocturnal attacks by the roaming infected, and sallies forth by daylight to kill the sleeping vampires. Every day he also makes repairs to his house, boarding up windows, stringing and hanging garlic, and disposing of vampires' corpses on his lawn.
Neville's psychological disposition is a significant element in the novel, and his struggles with despair imbue the character with intensity and gravitas. The author emphasizes that he is an ordinary, flawed man trying to deal with an extraordinary catastrophe.
Much of the story is devoted to Neville's struggles to understand the plague that has transformed everyone he meets except for himself, and the novel details the progress of his discoveries. In this regard, the novel is almost unique in vampire fiction in that instead of asking the reader to accept a supernatural explanation for vampire phenomena, the author strives to offer scientific basis for such symptoms as aversion to garlic, craving of fresh blood, and resistance to bullets but vulnerability to stakes and sunlight. The aversion to mirrors and crosses (or, in the case of one vampire of Jewish origin, the Torah) is classified as psychological.
Eventually, Neville discovers that while he is the only person immune to the bacterium, he is not the only one still alive. Others who have been infected have discovered a means to hold the disease at bay. However, during the daylight hours, they appear to be fully involved vampires. Thus, along with the vampires, he has been killing these still alive persons. He becomes a source of terror to the still living, since he can go abroad in daylight (which they can't) and leaves their dead behind. These still living “vampires” capture Neville and reveal their nature to him, and how monstrous he appears to them. Just as vampires were regarded as legendary monsters that preyed on the vulnerable humans in their beds, Neville has become the last of a dead breed; a mythical figure that kills both vampires and the infected living while they are sleeping. He becomes a legend as the vampires once were, hence the title.