In the summer of 1855, Sarah Brinton abandons her husband and child to make the long and difficult journey from Rhode Island to Minnesota Territory, where she plans to reunite with a childhood friend. When she arrives at a small frontier post on the edge of the prairie without family or friends and with no prospect of work or money, she quickly remarries and has two children. Anticipating unease and hardship at the Indian Agency, where her husband Dr. John Brinton is the new resident physician, Sarah instead finds acceptance and kinship among the Sioux women at a nearby reservation.

The Sioux tribes, however, are wary of the white settlers and resent the rampant theft of their land. Promised payments by the federal government are never made, and starvation and disease soon begin to decimate their community. Tragically and inevitably, this leads to the Sioux Uprising of 1862. During the conflict, Sarah and her children are abducted by the Sioux, who protect her, but because she sympathizes with her captors, Sarah becomes an outcast to the white settlers. In the end, she is lost to both worlds.

Intimate and raw, The Lost Wife is a brilliantly subversive tale of the conquest of the American West.