The narrator is a Christian, upper-class man living in London during the 1665 plague outbreak. He decides to remain in the city despite the spreading disease, convinced that God intends for him to stay. Throughout the crisis, he walks the streets to observe the changing conditions, gathers firsthand accounts, and tracks mortality statistics. He alternates between periods of strict self-isolation and venturing out to converse with others.

John is a working-class baker who spearheads a systematic plan to escape London and survive in the countryside. Lacking property or resources, he organizes a small group of tradesmen to camp in tents and abandoned barns. He serves as the unofficial spokesman and tactician for his group of refugees. He uses his persuasive skills to negotiate for provisions and secure charity from rural towns.

Thomas is a tradesman and John's brother who loses his livelihood when the plague halts city commerce. He is initially wary of leaving London because he lacks rural connections and fears rejection from country residents. He ultimately allows his brother to persuade him to join the wilderness expedition. He relies on his practical sail-making skills to help construct tents for the group's outdoor survival.

The narrator's brother is a wealthy London resident who owns a large house in the city as well as a country estate. He recognizes the severe threat of the outbreak early and makes practical arrangements to evacuate. Before departing, he attempts multiple times to persuade his stubborn sibling to join him in leaving. He ultimately leaves his large city home in the narrator's care.

Doctor Heath is a physician and personal friend of the narrator during the crisis. He understands the limited efficacy of public medical responses and focuses on practical prevention strategies. He advises the narrator to avoid close contact with others and maintain a constant indoor fire. His straightforward advice heavily influences the narrator's survival tactics.

The Joiner is a carpenter and friend of the baker and sail-maker. He pools his construction skills with the brothers to help build durable campsites in the countryside. He travels with them as they move through hostile towns and seek safe refuge.

The Boatman is a poor laborer who uses his vessel to run a delivery service on the river. He deliberately isolates himself from his sick wife and child to avoid catching the plague, dropping off money and supplies for them from a distance. He safely transports goods to wealthier families hiding on ships.

The Constable of Waltham is a local official tasked with protecting his town from the spreading infection. He intercepts Londoners trying to seek refuge in the countryside. He demands that traveling groups move along but provides them with basic provisions to ensure their departure.