Western expansion had a devastating impact on the Native Americans of the American West. The Native Americans of the region were time and time again pushed aside and relocated to new lands in order to make way for white settlers. Since the Washington administration, the United States government practiced the policy of purchasing Native American land through negotiating treaties. Most of these treaties strongly favored the government at the expense of the tribe. After the end of the Civil War, all of the Native Americans in the West were assigned to reservations that were administered by the US Army and Department of the Interior. Once relocated, it was the policy of the government to "civilize" the Native Americans. Educational programs were established to instruct the Native Americans of the West on how to give up their previous lifestyles and learn to homestead and ranch.

Of course, there were many Native Americans who refused to sign or abide by these treaties. Throughout the nineteenth century, there were a number of bloody conflicts, known collectively as the American Indian Wars. These wars almost always proved disastrous for the Native Americans and led to their brutal subjugation. In order to starve the Native Americans of the Great Plains, a hunting program was established that nearly wiped out the entire wild bison population. On a number of occasions, native civilians were attacked and killed by the army. A famous example of this is the Wounded Knee Massacre. On December 29, 1890, federal soldiers opened fire on a Sioux settlement on the Northern Lakota reservation. It resulted in the death of about three hundred Sioux women, children, and old men.

Through wars, disease, forced assimilation, and relocations, the Native American population of United States dropped dramatically over the course of the nineteenth century. Much of this was due to westward expansion and the idea of manifest destiny. It is thought that by the end of the century, fewer than 500,000 Native Americans still lived in the country.