From 1926 to 1938 he was the literary editor of the St. Louis Post-Dispatch. In 1931 he was given a leave of absence to conduct research for a poem about the massacre at Wounded Knee. While in South Dakota he befriended a holy man called Black Elk, a cousin of Crazy Horse. Neihardt’s interviews with him became the novel, Black Elk Speaks. It is considered one of the most important outsider accounts of Native American spirituality.

Neihardt became director of information for the Office of Indian Affairs during World War II, then accepted the position of poet in residence at the University of Missouri-Columbia. From 1952 to 1973, he was the Midwest regional vice president of the Poetry Society of America. At his funeral, a group of Sioux performed a ceremony of last rites rarely given to a white man.