The Lost Wife is a hard-hitting novella based in part on a white settler named Sarah Wakefield's memoir Six Weeks in the Sioux Tepees: A Narrative of Indian Captivity. In Susanna Moore's version of Wakefield's story, which opens in 1855, Sarah is a 25-year-old wife and mother who leaves her baby daughter, Florence, behind when she flees her abusive husband. She travels from Rhode Island to Minnesota Territory (encompassing present-day Minnesota and much of the Dakotas), where she hopes to meet up with an old friend and start a new life. Telling no one about her past, she marries Dr. John Brinton. The story then jumps forward to 1862, when Brinton is the doctor on a Sioux reservation and they have two children, four-year-old James and two-year-old Anne.

Although the Civil War is unfolding in the background, the greater threat in the territory is of a revolt by the Indigenous residents....