Will Sampson is a Native American professional photographer. He is forty and unmarried. The disappearance of his father has left him with unresolved emotional tensions. He is not only the narrator of the book but also the emotional center of the subtle social milieu of Medicine River. The other characters are defined by their interaction with Will. They establish an interpersonal atmosphere in the book that establishes a community whose whole is greater than the sum of its individual parts.
Harlen Bigbear is Will’s best friend. He is energetic and innovative and often motivates Will to do things he otherwise would not do.
Louise Heavyman is courted by Will. She has a daughter, South Wing. Louise is an imperfect yet sympathetic character. She communicates largely through subtle, indirect hints, though her emotional language is readily understood by Will.
Rose Sampson, Will’s mother, knows that Will has been affected by the disappearance of his mysterious and enigmatic father. She attempts to heal her son’s emotional wounds, but she can never quite succeed during her life. She has died when Will sets up his photography business in Medicine River, so she is presented exclusively in flashback.
Jake Pretty Weasel is an abusive husband who commits suicide. His fate highlights by contrast Will’s warmth toward Louise.
David Plume, a Native American militant, provides a contrast to the softspoken, nuanced character of Will. He also is a symbol of the lingering discontent felt among contemporary Native Americans.
Susan Adamson, a sophisticated Toronto woman who once was Will’s girlfriend, is an unsympathetic character who helps the reader to recognize the positive values held by Will and Louise at the end of the book. She is presented exclusively in flashback.