With two settings—one three centuries in the future and the other contemporary with Mary Shelley's own time—The Last Man combines elements of science fiction and fantasy. Lionel Verney, writing in the year 2100, believes he is the last human being left alive. Having completed a record of the events leading to the plague that wiped out humankind, he plans to set off alone, not knowing if others might survive in some distant land. (In the introduction, Mary Shelley states that these writings were found in 1818 in a cave where the sybils are thought to have lived. Thus, the "ancient history" documented therein also somehow occurs in the future.)
Lionel's memoir recounts his life at court in England's monarchy—and its abrupt end when the king dies and the queen banishes his family. The young outcast and his sister, Perdita, meet and befriend Prince Adrian, a bond that remains strong. Lionel later marries Adrian's sister, Idris, and Perdita marries Lord Raymond, who fought in a war between Greece and Turkey. Lionel, Adrian, and Raymond take up the Greek freedom fighters' cause and are lauded as heroes when they return. Raymond is found to be unfaithful, however, and then dies; the distraught Perdita kills herself. In contrast, Lionel and Idris have several children and a harmonious family life.
Adrian, whose branch of the royal family has been out of favor, decides to return to London. He is partly inspired to do this by the plague that is ravaging not only Europe but Asia and America as well. Adrian's excellence in leadership has a positive effect on morale, but that cannot stop the disease from spreading. Each day, thousands perish. Among them are Idris and one of her and Lionel's sons.
The handful of English survivors after the years of devastation include Lionel and his other son, as well as Adrian and Queen Clara. Sailing to France, the group finds equal devastation, with Paris left almost empty. A false prophet has gained a loyal following, but Adrian helps them see through his bad influence.
The English group continues on to Switzerland, and then to Italy, where Lionel's son dies. Their next destination is Greece, but en route by sea, their boat is wrecked, and only Lionel survives. At this point, safely back in Italy, Lionel devotes himself to penning this record. When he finishes, he will embark on a lone journey throughout Europe and Africa.