The plague is the most significant symbol of the novel, reflecting the theme of Humanity Versus Nature as it wrecks the human race and its civilizations. Though few but Lionel see the plague as something that has the potential to end the human race, others begin to realize toward the end of the novel that all attempts to stop it will be fruitless. The plague is thus a symbol for both the power of nature and the inevitability of the future.

Even in the early months of the plague, Lionel Verney notes its equalizing effects, mentioning how the wealthy have had to learn the skills of the poor to stay alive and that “there was nothing to prevent each from assuming possession of his share” (351) of the riches of the deceased aristocracy. As The Last Man is told from the point of view of the past, it is unclear whether any future generations of humans will repopulate the earth or learn from Lionel’s story that they have no power against the forces of nature.