Anderson employs the first person point of view. The fourteen-year-old protagonist, Mattie, gives readers the facts of Philadelphia and the epidemic quickly.

Anderson selected the title Fever 1793 because the story occurs during the period when Philadelphia suffered severe losses from the 1793 yellow fever epidemic. Set in the post-Revolutionary era, the story explores the worldwide themes of friendship and death. As Mattie matures, she learns perseverance, hope, and self-reliance.

Mattie is in conflict with her mother, at odds with her body, and is dreaming about her future when she hears about the death of her childhood friend Polly. Shocked, she finds little time to grieve as she helps her mother serve coffeehouse clients. Confused about what killed Polly, Mattie and her family begin to hear about yellow fever but quickly dismiss the predictions as pessimistic.

Readers learn in the first chapter about Mattie's crush on Nathaniel Benson...