Born in Belgium, De Smet came to the United States and entered the Society of Jesus for the purpose of serving in frontier missions. He helped to found the Missouri Province of Jesuits at Florissant, then inaugurated missions among Indians of the Plains and Rockies: Sioux (Dakotas and Lakotas), Coeur d'Alenes, Flatheads, Pend d'Oreilles, and Blackfeet. He also worked for a time at St. Louis University, in which city he died.