On April 25, 1805, the Corps of Discovery camped near the confluence of the Yellowstone and Missouri rivers, close to where Fort Union Trading Post would later be built, and noted the spot's potential as a major trade location linking two navigable river "highways of commerce." At that time they were still a short distance east of the present Montana border; they entered what is now eastern Montana two days later, on April 27, 1805, after moving a few miles upstream from the future fort site.

Between 1828 and 1829, at the request of the Assiniboine, the American Fur Company established Fort Union near this same confluence, and from about 1828/1829 until 1867 it became the most important fur trading post on the upper Missouri River. Assiniboine, Crow, Cree, Ojibwe, Blackfeet, Hidatsa, Lakota, and other Northern Plains tribes regularly brought buffalo robes and furs to Fort Union and exchanged them for manufactured goods such as cloth, guns, beads, blankets, knives, cookware, and occasionally alcohol.

Lewis and Clark did not meet the Blackfeet during their 1805 passage by the future fort site; their first documented encounters and the well-known conflicts with Blackfeet groups occurred later in the expedition, particularly during the return journey in 1806, so historians are careful not to project those later tensions back onto the 1805 campsite at the Yellowstone-Missouri confluence.