In the 19th century, the incessant Westward expansion of the United States incrementally compelled large numbers of Native Americans to resettle further west, sometimes by force, almost always reluctantly. Under President Andrew Jackson, Congress passed the Indian Removal Act of 1830, which authorized the President to conduct treaties to exchange Native American land east of the Mississippi River for lands west of the river. As many as 100,000 Native Americans eventually relocated in the West as a result of this Indian Removal policy. In theory, relocation was supposed to be voluntary (and many Native Americans did remain in the East), but in practice great pressure was put on Native American leaders to sign removal treaties. Arguably the most egregious violation of the stated intention of the removal policy was the Treaty of New Echota, which was signed by a dissident faction of Cherokees, but not the elected leadership. The treaty was brutally enforced by President Martin Van Buren, which resulted in the deaths of an estimated 4,000 Cherokees (mostly from disease) on the Trail of Tears.

Conflicts, generally known as "Indian Wars", broke out between U.S. forces and many different tribes. U.S. government authorities entered numerous treaties during this period, but later abrogated many for various reasons. Well-known military engagements include the Native American victory at the Battle of Little Bighorn in 1876, and the massacre of Native Americans at Wounded Knee in 1890. On January 31, 1876, the United States government ordered all remaining Native Americans to move into reservations or reserves. This, together with the near-extinction of the American Bison that many tribes had lived on, set about the downturn of Prairie Culture that had developed around the use of the horse for hunting, travel and trading.