As the Corps entered the Great Plains, new animals previously unknown such as the coyote and antelope were recorded for the first time. In addition, it was in South Dakota where Lewis and Clark first recorded large herds of buffalo that came to symbolize the Great Plains.

As the Corps sailed north, they met up with the Teton Sioux Indians near present-day Pierre, South Dakota. The Teton Sioux had previously been documented as powerful and aggressive by French fur-traders and often required payments or tributes to traders or other native groups for safe passage up the river. When the Corps first encountered the Teton Sioux, they attempted to demonstrate power and might by firing one of their air guns and parading in uniform. The Teton Sioux, however, were neither frightened nor impressed, and demanded one of Corps' boats as a toll for moving farther upriver. A fight nearly ensued, but was defused by the diplomacy of a chief named Black Buffalo after the Corps of Discovery offered tobacco as a tribute. For three more anxious days, the expedition stayed with the tribe, where there were celebrations, misunderstandings, and an overall lack of communication, as neither side properly understood the other. During this time, William Clark took detailed notes about the Teton Sioux, remarking that they were generally thin and ill-looking in appearance. He also took notes describing a "scalp dance" performed by the tribe after a war victory over the rival Omahas.