Sandoz's life as a student and teacher in rural Nebraska—a rigorous life that left her blind in one eye from a blizzard at age 13—prepared her to depict realistically pioneer and Indian life. She wrote almost 80 stories while in college, but her first success came when she was in her mid-30s, with Old Jules (1935), a story of her father's hard farm life.

Sandoz's books include Crazy Horse (1942), a biography of the Sioux Indian chief; Cheyenne Autumn (1953), which concerns Indians leaving a reservation, to which they had been sent by the U.S. Army, in order to return home; The Buffalo Hunters (1954), which tells of the white settlers' slaughter of bison and its social impact on the West; and The Battle of the Little Bighorn (1966). These works are praised for their accurate re-creation of character and historical events.