Native American tribes had different relationships with colonial settlers, toggling between conflict and treaties. From 1778 to 1871, there were over 368 treaties between tribes and the US government, mostly broken. After US independence, the US policy towards Native Americans grew aggressive, and President Jackson's Indian Removal Act of 1830 led to the forced relocation of Tribes to the American West; the outcome was the Trail of Tears. Indian Appropriations Acts created the reservation system, which made people noncitizens (until 1924), with limited rights and ability to travel and work off reservations that had limited economic activity. Reservations began to shrink by the 1870s with the "Sell or Starve" Act seizing the Black Hills (7 million acres) from the Sioux Nation in 1877. The Dawes Act of 1887 split communal tribal land into family allotments that could be sold. Land allotment was predicated on a high enough Blood Quantum or someone's percentage of "Indian blood." Blood quantum was used to limit tribal membership and eligibility for land allotments, reducing the size of reservations and tribes. From the Dawes Act until 1934, over 60 million acres of land were taken and sold, so many reservations have shrunk and are checkerboarded with private non-native owners, including for extractive industries including petroleum, natural gas, and more recently, lithium. The Killers of the Flower Moon is an example of this process of land theft.

In addition to the Reservation System, the US government opened off-reservation Boarding Schools, beginning with the Carlisle Industrial Indian School (in 1877) for native children. These schools claimed to "Kill the Indian, Save the Man" by an early advocate of the schools, Captain Richard Henry Pratt. The schools focused on forced cultural assimilation and involved brutality.

The Heard Museum has an online exhibit about Boarding schools called Away from Home.

While most schools have closed, by 2022, unmarked burial sites have been found on 53 school grounds. As Boarding Schools waned, more children on reservations were taken by child welfare workers for fostering and adoptions; on some reservations, the rates were one-third to one-half of children were placed off reservations, often against the knowledge and wishes of parents and family members. The Indian Child Welfare Act of 1978 (ICWA) reduced the number of off-reservation and non-native child welfare placements. However, ICWA has been challenged in court (as of 2023, it still stands), and some states still have high rates of child removals and off-reservation placements.