Though educated as a psychologist (Ph.D., Columbia University, 1901), Wissler was drawn to anthropology through the influence of Franz Boas (Boas, Franz). Wissler was curator of the American Museum of Natural History in New York City for nearly 40 years and also taught at Yale University (1924–40).

North American Indians of the Plains (1912) reflects the main focus of his fieldwork. He became a leading authority on the Dakota, or Sioux, and Blackfoot peoples, writing more than 200 scientific and popular articles and books, notably (with D.C. Duvall) Mythology of the Blackfoot Indians (1908, reissued 1995). His descriptions particularly noted material culture, myths and tales, art designs, social organization and ethical values, and especially the spectacular Sun Dance religious ceremony.

At the American Museum, Wissler arranged collections and exhibits according to area and group. In The American Indian (1917), a classic in North American ethnology, he explored the regional clustering of cultural traits and the relation between culture and physical environment, outlining the main culture areas. The distribution and adaptation of cultural traits and their relative ages were treated in Man and Culture (1923) and The Relation of Nature to Man in Aboriginal America (1926). His later works include Indian Cavalcade (1938) and Indians of the United States (1940).