Archaeological evidence shows periodic Native American residence in this general area for some 12,000 years. From the mid-1600s to the early 1700s the Omaha, Ponca, Oto, and Ioway migrated from the Upper Midwest and Great Lakes to today's western Iowa and eastern Nebraska. The Pawnee were the only Native Americans then living in the region. In the 1860s the Winnebago and Santee Sioux were relocated to Nebraska.
From the 1730s to the 1760s the Oto occupied an earthlodge village extending from today's Creighton campus to downtown Omaha. In 1804 Lewis and Clark recorded the ruins as "ancient village of the Ottoes on mounds." Jesuits began work among North America's Native peoples in the 1600s, and in 1829 opened a mission center in St. Louis. In 1838-39 Father Pierre J. DeSmet and other Jesuits founded St. Joseph's Mission for the Potawatamie tribe across the Missouri River from here.
Although the Pawnee, Oto-Missouria, and Iowa nations now reside elsewhere, the Omaha, Northern Ponca, parts of the Winnebago and Santee Sioux, and a significant urban Indian population in Omaha and other Nebraska cities remain Creighton's neighbors and partners.