In Fever 1793, Mattie lives with her mother and grandfather in Philadelphia, where her family runs a coffee house. Initially when her mother falls ill, Mattie, who is fourteen, stays with her and cares for her. The herbalist who attends Mattie's mother misdiagnoses her, for a fee. After a real doctor sees her and identifies yellow fever, the family decides that the grandfather and Mattie should leave the city to escape the epidemic.

On the way out, however, Mattie's grandfather's cough seems like a symptom, so they get thrown off the wagon out in the countryside. While trying to get help, Mattie collapses. It turns out that she (not her grandfather) has yellow fever. He has carried her to a makeshift hospital.

Once Mattie recovers sufficiently, they return to the city to look for her missing mother, who has left their house locked up and empty. By then the coffeeshop has been looted, and they have little food. One night, as they chase off some intruders, her grandfather dies, and Mattie is left alone. She makes her way across town to the African American section where their servant Eliza lives and finds her.

As weeks go by without word of her mother, Mattie helps Eliza care for children orphaned by the epidemic, housing them in the coffeeshop. As her friendship with Nathaniel matures into romance, the epidemic finally ends. After Mattie decides to reopen the coffeeshop, and Eliza agrees to be her partner, at last her mother returns. She is astonished to see how much her daughter grew up in just a couple months. She is part of a large group returning from the countryside along with George Washington.