Fever 1793 takes place in Philadelphia during the yellow fever epidemic of 1793. This was the first major outbreak of yellow fever in the United States. It hit Philadelphia in the summer of 1793, following the Revolutionary War, and peaked in October of that year.

The book contains many accurate historical details. For example, at that time, Philadelphia was serving as the temporary capital of the country, and Congress was located in the city. In addition, Eliza, the cook at Mattie's family's coffee house, is a free African American. There were many free African Americans in Philadelphia at the time. The Quakers who ran Philadelphia were opposed to slavery. Dr. Benjamin Rush, a figure in the novel, was a real-life physician and signer of the Declaration of Independence who tried to cure fever victims by bloodletting them and administering mercury, perhaps doing more harm than good. He recruited African American volunteers to help the fever victims, as he falsely believed that African Americans were immune to the epidemic. Many African Americans, such as Absalom Jones and Richard Allen, valiantly helped nurse victims. 

The story Fever 1793 takes place in Philadelphia during the post-Revolutionary War years.  Philadelphia was the capital of the newly formed United States at that time, and the events described take place during a four-month period, from August to November, in 1793.  Fever 1793 is historical fiction, meaning that, although the main characters are not real, the story and setting are firmly based on events that really happened.

The author vividly recreates the feeling of eighteenth-century Philadelphia, culturally, topographically, and politically.  The reader is placed in the midst of the bustling city, surrounded by horses and carriages, small businesses, and friendly neighbors (and their pets) going about their daily routine.  From the coffeehouse where Mattie, the main character, lives and works, the State House where Congress meets can be seen, as well as the home of President Washington, and, farther away, the ships on the docks on the Delaware River.  In the coffeehouse itself, citizens and politicians alike gather to talk about the issues of the day, and there are ample references to important people who lived during those times, as well as significant events.  Some of these famous persons include Dr. Jean Deveze and Dr. Benjamin Rush, who held opposing views on how fever victims should be treated; some significant events mentioned, in addition to the yellow fever epidemic of course, are the launching of Blanchard's hot air balloon and the brave activities of the African Free Society.