Reservation Blues is set in 1992 on the Spokane Indian Reservation. The novel begins with the rare arrival of a stranger to the reservation, a black man who stands at the crossroads, waiting with his guitar. Thomas Builds-the-Fire, who is driving by, stops to talk to the man. Thomas is 32 years old, dark skinned, and “marked by loneliness, like some red L was tattooed on his forehead” (Chapter 1). A bit of an outsider, Thomas is known for telling stories. He learns that the stranger’s name is Robert Johnson and that he is searching for a woman he has seen in dreams who he believes may be able to help him. Years ago, Johnson sold his soul to a figure he calls “the Gentleman,” from whom he has been trying to hide since faking his death in 1938. Thomas takes Johnson to Wellpinit Mountain so he can climb to Big Mom’s home on the mountaintop.

The omniscient narration then switches to Big Mom’s perspective. Big Mom remembers a time over a hundred years ago, when the Indian horses were brutally slaughtered by soldiers.