Prior to first contact with European colonizers, around 10 million Native Americans lived on the North American continent. They lived in diverse and distinct groups, each with a unique culture and varied languages and religion. Following their first contact with Europeans in the 1500s and early 1600s, Native Americans in the Caribbean and other areas responded to the seizure and settlement of their land in various ways. Some cooperated with the European settlers, while others responded with violent resistance. However, because of disease brought by the Europeans, Native American populations were decimated. Diseases like smallpox spread quickly among Native Americans and wiped out entire villages. Several large epidemics occurred in the 17th and 18th centuries among the Native American populations, making it difficult to mount an opposition to European colonial expansion.

Still, the resistance continued during the colonial period. Some Native American nations made wartime alliances, such as during the French and Indian War, and land-sharing agreements with European colonizers, but neither government leaders nor individual settlers kept their promises to keep off Native American land. Despite this, Native Americans maintained their traditions against this challenge to their physical and cultural survival. Later, the new U.S. government engaged in a wide array of genocidal actions, from pushing Native Americans off their land in the east using callous methods such as the Trail of Tears, to forcing Native American children into Indian boarding schools, to destroying the bison on which the livelihood of western Native Americans depended.

In the 17th century, some European colonizers formed alliances with Native Americans to gain advantages in conflicts, such as the Beaver Wars. Native American nations used these alliances strategically to cause friction among Europeans. The Iroquois Confederacy was particularly adept at pitting European powers against each other to maintain their influence. During the French and Indian War of 1754–63, some Iroquois nations sided with England, while many Algonquian-speaking nations allied themselves with France. The English won the war and claimed all of the land east of the Mississippi River. At the end of the war, the British and the Native Americans agreed to the Proclamation of 1763, which limited European settlement to east of the Appalachian Mountains. The Iroquois and other allied Native American groups expected that this would end European expansion.

However, the British government and settlers did not follow the Proclamation of 1763 and continued to push west and take land from Native Americans. Some of the broken treaties may have resulted from misunderstandings, as many Native American nations had a communal view of land ownership and may have assumed that the agreements provided access to the land rather than an exclusive right to it. However, many treaties were knowingly and purposefully broken by the European colonial governments that had signed them as part of the ongoing seizure of Native American land and resources.

While some nations at least briefly benefitted from participation in European conflicts, the costs to others were extremely harmful. Following the wars between the European nations, Native Americans that allied with the losing side were often enslaved or forcibly removed from their land. In South Carolina, for example, some Native Americans were captured and sold into slavery in places such as Canada, threatening their culture and very existence.

At the same time, Europeans exploited existing rivalries among different Native American nations. French traders made alliances with the Huron and Algonquin nations to access the beaver fur trade, which had a very lucrative market in Europe. These Native American nations had specific knowledge of trapping beavers that the French did not. At various times, the French showed favor to one tribe over another, providing more weapons to nations, like the Huron, whose members converted to Christianity, a tactic to assimilate Native Americans to European culture. Europeans, too, used the French and Indian War to stir up existing conflicts between the Iroquois and Algonquian nations. Calculated actions like these caused rifts that kept some Native American tribes from working together to stop European takeover.

European colonizers were also a continuing threat to Native American culture during this time. In addition to losing traditions and knowledge due to widespread death, Christian groups began to force conversion onto Native Americans in return for teaching them new skills. Like the French who converted the Huron, Spanish Christian leaders forced Native Americans in what would later become California into walled-off communities. These communities, called missions, were intended to spread Christianity, which was part of the duty of being a Christian. It also served to make Native Americans adopt European culture along with religion.

The American Revolution ushered in a new government and new treaties. However, the U.S. government repeatedly broke these agreements by continuing to seize Native American land.

Today, many people have called for land reparations to return land seized during European settlement of North America. Native American-led actions, such as the Land Back movement, have challenged the U.S. government to return parts of ancestral land back to the nations who originally lived there. Their advocacy has led to some gains: in 2023, almost 1.2 million hectares (3 million acres) of land was returned to 50 Native American nations in 15 states. They continue to push for broader reparations, not only to reclaim lost land but also to address deep historical injustices, including the loss of life, culture and sovereignty.