The first treaty between the tribe and the United States government was made at Fort Harmar, Ohio, the Commandant at the fort, Arthur St. Clair, being Commissioner on the part of the United States. This, like the treaty negotiated at Greenville by General Anthony Wayne on August 3, 1795, the one negotiated at Fort Wayne by William Henry Harrison in June, 1803, and several that succeeded, was a treaty of peace and settlement of boundaries with the Potawatomie, in common with the Wyandot, Delaware, Shawnee, Ottawa, and other tribes. At the Greenville Treaty, the first annuities were paid the Potawatomie, the amount being $1,000. This treaty was signed by the chiefs of the Potawatomie of the River St. Joseph and of the Potawatomie of Huron.

During the war of 1812 with Great Britain, a portion of the tribe allied themselves with that nation, and under the leadership of Sunawe-wone, Chief of the Prairie Band, made war upon the Americans, and were engaged in the Massacre at Fort Dearborn in present-day Chicago. A treaty was made with this band at Portage des Sioux, on July 18, 1815, William Clark, Ninian Edwards and August Choteau being United States Commissioners. By the terms of this treaty, the tribe again placed themselves under the protection of the United States, were reinstated in their privileges, and solemnly agreed to preserve "perpetual peace and friendship" with the Americans. The treaty was signed by Sunawe-wone, and it is said that it was never broken by his band. The following September, a general treaty with the remainder of this tribe and others was made near Detroit, Michigan.

By the treaty of August 29, 1821, at Chicago, the Potawatomie of the St. Joseph River, Michigan, ceded a large portion of their land, reservations being granted to John, James, Abram, Rebecca and Nancy Burnett, "which are children of Kaw-kee-me, sister of Top-ni-be," principal chief of the Pottawatomie nation. Land was also reserved to the Bertrands and the Beaubiens.

On September 26, 1833, a treaty was concluded at Chicago, by which the United Potawatomie, Ottawa and Chippewa tribes ceded to the United States about five million acres. By this treaty, the Potawatomie were assigned a tract between the Mississippi and Missouri Rivers for a permanent home. Their first location was in the irregular triangle afterward known as the "Platte Purchase," then a part of the Indian Territory. In 1836, the land thus occupied became a part of Missouri, and those of the Potawatomie who had removed to the reservation, numbering between 1,000-2,000, again removed to a tract above the northern line of Missouri, in what is now Southwest Iowa, their village being on the river near the present site of Council Bluffs.