A series of efforts were made by the United States to assimilate Native Americans into mainstream European–American culture between the years of 1790 and the 1960s. George Washington and Henry Knox were first to propose, in the American context, the cultural assimilation of Native Americans. They formulated a policy to encourage the so-called "civilizing process". With increased waves of immigration from Europe, there was growing public support for education to encourage a standard set of cultural values and practices to be held in common by the majority of citizens. Education was viewed as the primary method in the acculturation process for minorities.

Americanization policies were based on the idea that when Indigenous people learned customs and values of the United States, they would be able to merge tribal traditions with American culture and peacefully join the majority of the society. After the end of the Indian Wars, in the late 19th and early 20th centuries, the federal government outlawed the practice of traditional religious ceremonies. It established Native American boarding schools which children were required to attend. In these schools they were forced to speak English, study standard subjects, attend church, and leave tribal traditions behind.

The Dawes Act of 1887, which allotted tribal lands in severalty to individuals, was seen as a way to create individual homesteads for Native Americans. Land allotments were made in exchange for Native Americans becoming US citizens and giving up some forms of tribal self-government and institutions. It resulted in the transfer of an estimated total of 93 million acres (380,000 km²) from Native American control. Most was sold to individuals or given out free through the Homestead law, or given directly to Indians as individuals. The Indian Citizenship Act of 1924 was also part of Americanization policy; it gave full citizenship to all Indians living on reservations. The leading opponent of forced assimilation was John Collier, who directed the federal Office of Indian Affairs from 1933 to 1945, and tried to reverse many of the established policies.

Epidemiological and archeological work has established the effects of increased immigration of children accompanying families from Central Africa to North America between 1634 and 1640. They came from areas where smallpox was endemic in Europe, and passed on the disease to indigenous people. Tribes such as the Huron-Wendat and others in the Northeast particularly suffered devastating epidemics after 1634.

During this period European powers fought to acquire cultural and economic control of North America, just as they were doing in Europe. At the same time, indigenous peoples competed for dominance in the European fur trade and hunting areas. The European colonial powers sought to hire Native American tribes as auxiliary forces in their North American armies, otherwise composed mostly of colonial militia in the early conflicts. In many cases indigenous warriors formed the great majority of fighting forces, which deepened some of their rivalries.

To secure the help of the tribes, the Europeans offered goods and signed treaties. The treaties usually promised that the European power would honor the tribe's traditional lands and independence. The indigenous peoples formed alliances for their own reasons, wanting to keep allies in the fur and gun trades, positioning European allies against their traditional enemies among other tribes, etc. Many Native American tribes took part in King William's War (1689–1697), Queen Anne's War (1702–1713) (War of the Spanish Succession), Dummer's War (c. 1721–1725), and the French and Indian War (1754–1763) (Seven Years' War).

As the dominant power after the Seven Years' War, Great Britain instituted the Royal Proclamation of 1763, to try to protect indigenous peoples' territory from colonial encroachment of peoples from east of the Appalachian Mountains. The document defined a boundary to demarcate Native American territory from that of the European-American settlers. Despite the intentions of the Crown, the proclamation did not effectively prevent colonists from continuing to migrate westward. The British did not have sufficient forces to patrol the border and keep out migrating colonists. From the perspective of the colonists, the proclamation served as one of the Intolerable Acts and one of the 27 colonial grievances that would lead to the American Revolution and eventual independence from Britain.

The most important facet of the foreign policy of the newly independent United States was primarily concerned with devising a policy to deal with the various Native American tribes it bordered. To this end, they largely continued the practises that had been adopted since colonial times by settlers and European governments. They realized that good relations with bordering tribes were important for political and trading reasons, but they reserved the right to abandon these good relations to conquer and absorb the lands of their enemies and allies alike as the American frontier moved west.