After the plague arrives from Holland to England between September and November of 1664, the narrator's brother tries to compel him to flee the city and go to the country (as many of the wealthy do). The narrator chooses instead to trust his health and safety to God and feels that fleeing the city would be fleeing from God. The narrator unequivocally attributes the plague to God's work.

The journal reflects not only the private thoughts of the narrator, but also stories he hears or encounters during the year of the plague. Many turn to wearing charms to defend against the plague. The narrator cannot believe the number of professed witches and "quack" doctors who claim to be able either to predict one's future or cure the plague. A fearful population keep papers with spells such as "abracadabra" written thereon. People's despair leads their imaginations to see apparitions that are not there. The narrator considers it folly to suppose that the plague is caused by an evil spirit, and thus able to be exorcised, rather than the result of God's wrath.

Finally, disease brings out the worst in people. The narrator remembers when a group of men (accustomed to sitting outside of a church, drinking) mocked him as he prayed. They claimed that he did not deserve to live as so many honest men died.

As a practical matter, the narrator supposes that the disease entered houses by means of the servants, who were regularly sent among the crowded streets. The narrator also laments the circumstance that there was only one "pest-house" (for plague sufferers) in the city. The narrator records that, during the height of the plague (which killed hundreds of thousands according to modern estimates), a thousand people died each day.