He is known primarily for his widespread missionary work in the mid-19th century among the Native American peoples, in the midwestern and northwestern United States and western Canada.

He was affectionately known as "Friend of Sitting Bull", as he persuaded the Sioux war chief to participate in negotiations with the American government for the 1868 Treaty of Fort Laramie.

De Smet and five other Belgian novices, led by Charles Van Quickenborne, moved to Florissant at the invitation of bishop Louis William Valentine DuBourg.

[4] In 1838 and 1839, De Smet helped to establish St. Joseph's Mission in what is now Council Bluffs, Iowa, in Potawatomi territory along the Upper Missouri River.

Taking over the abandoned Council Bluffs Blockhouse at the former United States military fort, De Smet worked primarily with a Potawatomi band led by Billy Caldwell, also known as Sauganash.

De Smet was appalled by the murders and brutality resulting from the whiskey trade, which caused much social disruption among the Indian people.

[5][6] After discussion with Iroquois fur trappers who had come from the Montreal area to the Pacific Northwest, the Salish Native Americans had gained a slight knowledge of Christianity.

Three times they sent delegations of their tribe more than 1,500 miles (2,400 km) to St. Louis to request "black-robes" from the Catholic Church to come to baptize their children, sick, and dying.

The first two delegations reached St. Louis after being devastated by sickness, and although Bishop Joseph Rosati promised to send missionaries when funds were available, he never did.

On 5 July 1840, De Smet offered the first Mass in Wyoming, a mile east of Daniel, a town in the west-central part of the present state.

He noted that the Protestant proselytizing of the American Board of Commissioners for Foreign Missions under Henry H. Spalding, based at Lapwai, had made the neighboring Nimíipuu (Nez Perce) nation wary of Catholicism.

Near the end of his time with the Salish, De Smet sent out an appeal to the United States public for financial aid to bolster his missionary efforts.

"[9] He went back to France to recruit more workers, and returned to the Pacific Northwest via Cape Horn, reaching the Columbia River on 31 July 1844 with five additional Jesuits and a group of Sisters of Notre Dame de Namur.

[4] One of De Smet's longest explorations began in August 1845 in the region west of the Rockies that was jointly occupied by the Americans, who called it Oregon Country, and the British, who identified it as Columbia District.

De Smet started from Lake Pend Oreille in present-day north Idaho and crossed into the Kootenay River Valley.

[10] In the spring of 1846, De Smet began his return westward, following the established York Factory Express trade route to the Columbia District.

He then crossed the Great Divide by Athabaska Pass, traveling to the Canoe_River_(British_Columbia), the northernmost tributary of the Columbia River, and eventually on to Fort Vancouver, some thousand miles (1600 km) to the southwest.

De Smet returned to St. Louis and from there made several trips to the north country helping Indians and teaching Christianity.