The book's narrator, H. F., a saddler, decides that it is God's will that he stay in London during the outbreak of the plague in 1665. The book combines (what most scholars agree is) a very accurate account of the plague year with the story of H. F.'s spiritual development as a result of his encounter with the stresses brought on by the plague. It also includes many apt insights on human nature in times of distress.

H. F.—as an eyewitness who watched terrified people, mostly the poor who had no means to leave London—notes how easily the people were swayed by quack physicians who promised them cures at high prices, although there was no evidence that these cures would in any way work. The people preferred to pay those who told them what they wanted to hear rather than legitimate physicians:

But to return to the people, whose confusions fitted them to be imposed upon by all sorts of pretenders and by every mountebank. There is no doubt but these quacking sort of fellows raised great gains out of the miserable people, for we daily found the crowds that ran after them were infinitely greater, and their doors were more thronged than those of Dr Brooks, Dr Upton, Dr Hodges, Dr Berwick, or any, though the most famous men of the time.

The quote below shows the scrupulous accuracy with which H. F. describes a rapid uptick in plague deaths in August and September, a period during which many people died quickly. H. F. also refutes a misconception that people were left unburied because of a lack of people to bury them. Instead, he says, whole groups died at once, meaning that there was nobody left to alert the authorities:

Many houses were then left desolate, all the people being carried away dead . . . and some that died last in several of those houses were left a little too long before they were fetched out to be buried; the reason of which was not, as some have written very untruly, that the living were not sufficient to bury the dead, but that the mortality was so great in the yard or alley that there was nobody left to give notice to the buriers or sextons that there were any dead bodies there to be buried. It was said, how true I know not, that some of those bodies were so much corrupted and so rotten that it was with difficulty they were carried

H. F. also takes time to ruminate on how the threat of imminent death brings people together. People crowded into churches and did not, as usually was the case, care if the people around them were Dissenters (people who did not belong to the Church of England). In fact, H. F. points out that, since many of the Church of England's clergy had fled to the countryside, it was sometimes left to the Dissenting preachers to perform the services. The people who once persecuted Dissenters, H. F. wryly notes, now had no problem inviting them into to preach. H. F. then predicts that another plague year would bring people together in harmony. He notes that death has a way of erasing petty differences:

Here we may observe and I hope it will not be amiss to take notice of it that a near view of death would soon reconcile men of good principles one to another, and that it is chiefly owing to our easy situation in life and our putting these things far from us that our breaches are fomented, ill blood continued,...