The narrative concerns Europe in the late 21st century, ravaged by the rise of a bubonic plague pandemic that rapidly sweeps across the entire globe, ultimately resulting in the near-extinction of humanity.

It also includes discussion of the British state as a republic, for which Shelley sat in meetings of the House of Commons to gain insight to the governmental system of the Romantic era.

The orphan son of an impoverished nobleman, Lionel is originally lawless, self-willed, and resentful of the nobility for casting aside his father.

Lucy Martin: A young woman who chose to marry a repulsive suitor rather than wait for her true love, to provide for her ageing mother.

The Imposter: Unnamed – a false prophet (from ambition, rather than fanaticism) who creates a radical religious sect in opposition to Adrian while in France.

Mary Shelley states that in 1818 she discovered, in a cave near Naples, prophetic writings painted on leaves by the Cumaean Sibyl.

Lord Raymond, who came to be renowned for his exploits in a war between Greece and Turkey,[3] has returned to England searching for a political position.

Raymond attempts to support Evadne by employing her artistic skills in secrecy, and later nursing her in illness, but Perdita learns of the relationship and suspects infidelity.

Perdita refuses to leave Greece, but Lionel drugs her and brings her aboard a steamship, believing it to be in the best interests of Clara.

The appearance of a black sun causes panic throughout the world, and storm surges flood coastal towns across Europe.

Ryland, recently elected Lord Protector, is unprepared for the plague, and flees northward, later dying alone amidst a stockpile of provisions.

On the eve of their departure to Dover, Lionel receives a letter from Lucy Martin, who could not join the exiles because of her mother's illness.

In France, Adrian learns the earlier emigrants have divided into factions, amongst them a fanatical religious sect led by a false messiah who claims his followers will be saved from disease.

The survivors attempt to sail across the Adriatic Sea from Venice to Greece, but a storm destroys the boat and drowns Clara and Adrian.

Fearing to be the last human left on Earth, Lionel follows the Apennine Mountains to Rome, befriending a sheepdog along the way.

A year passes without anyone else entering Rome, and Lionel resolves to leave with his dog and live the rest of his life as a wanderer of the depopulated continents of Africa and Asia looking for other survivors.

[1] It appears that Shelley found inspiration for the title of her novel in Jean-Baptiste Cousin de Grainville's Le Dernier Homme (1805), translated into English in 1806 as Omegarus and Syderia.

[8] The Last Man not only laments the loss of Shelley's friends, but also questions the Romantic political ideals for which they stood.

"[11] Specifically, Mary Shelley, in making references to the failure of the French Revolution and the Godwinian, Wollstonecraftian, and Burkean responses to it, "attacks Enlightenment faith in the inevitability of progress through collective efforts".

[12] Hugh Luke argues, "By ending her story with the picture of the Earth's solitary inhabitant, she has brought nearly the whole weight of the novel to bear upon the idea that the condition of the individual being is essentially isolated and therefore ultimately tragic" (xvii).

Shelley's construction of Lionel Verney's immunity remains a subject of significant critical debate, but the novel certainly demonstrates a deep understanding of the history of medicine, specifically the development of the smallpox vaccine and the various nineteenth-century theories about the nature of contagion.

[15] Eileen Hunt Botting of the University of Notre Dame has stated that the novel "saw that the disaster of a pandemic would be driven by politics," and that the "spiraling health crisis would be caused by what people and their leaders had done and failed to do on the international stage—in trade, war and the interpersonal bargains, pacts and conflicts that precede them.

"[16] Botting has further described the novel as identifying "three patterns of modern democratic corruption, which would be exposed and exacerbated by a pandemic: 1. slow yet steady institutional erosion of norms and practices of trust and equality; 2. authoritarian forms of populism that betray the people who bring an executive leader to power; and 3. patriarchal and religious forms of populism that manipulate the people's beliefs through fear and disinformation.

According to Olivia Murphy of the University of Sydney, the novel shows that "this sense of racial superiority and immunity is unfounded: all people are united in their susceptibility to the fatal disease.

Individual reviewers labelled the book "sickening", criticised its "stupid cruelties", and called the author's imagination "diseased".

[18] Rebecca Barr of the University of Cambridge wrote that the novel was "an astonishing work" that "resonates with contemporary feelings of climate grief as well as the sense of helplessness as we confront COVID-19.

"[23] Eileen Hunt Botting of the University of Notre Dame described the book as Shelley's "second great work of science fiction," saying that it provided "an existential mind-set for collectively dealing with the threat of a global man-made disaster.