It was as President of the United States that Thomas Jefferson had the greatest impact on the Native American Nations of North America. He pursued a policy towards Indigenous people that had two main ends. First, Jefferson wanted to guarantee the security of the United States and so sought to bind Indigenous Nations to the United States through treaties. The aim of these treaties was to acquire land and facilitate trade, but most importantly to keep them allied with the United States and not with European powers, namely England in Canada and Spain in the regions of Florida, the Gulf Coast and lands west of the Mississippi River. Secondly, Jefferson used the networks created by the treaties to further the program of gradual "civilization." His Federalist predecessors had begun this program, but it was completely in keeping with Jefferson's Enlightenment thinking. Through treaties and commerce, Jefferson hoped to continue to get Native Americans to adopt European agricultural practices, shift to a sedentary way of life, and free up hunting grounds for further white settlement.

The desire for land raised the stakes of the "civilization program." Jefferson told his agents never to coerce Indigenous Nations to sell lands. The lands were theirs as long as they wished, but he hoped to accelerate the process. In a letter to William Henry Harrison, written as the diplomatic crisis leading to the Louisiana Purchase unfolded, Jefferson suggested that if the various Indian nations could be encouraged to purchase goods on credit, they would likely fall into debt, which they could relieve through the sale of lands to the government. The Louisiana Purchase itself would forever change the fate of many nations, and opened up the west for Jefferson’s vision of expanding white settlement and Indigenous acculturation or removal.

During The Corps of Discovery Expedition, Lewis and Clark would carry Jefferson’s vision to the Tribal Nations of the west. Recognizing their extreme vulnerability, Jefferson urged diplomatic caution when Lewis and Clark were treating with distant Tribal Nations, and his scientific and cultural interests led to his excitement in receiving shipments of diplomatic trade items from those western Nations. He later displayed many of these at Monticello, preserving them as examples of Indigenous ingenuity and artistic quality. But he still considered Native cultures in need of “civilization,” and sought to enact policies that would encourage Native peoples to adopt Euro-American practices, including debt accrual and the sale of land in exchange for what he considered would be their betterment. The "civilization program" would thus aid the Native Americans in accordance with Enlightenment principles and at the same time further white interests. Indigenous peoples were divided as to how to respond to Jefferson's policies.

The Shawnee chief Black Hoof embraced the "civilization program," and he and many Shawnee settled within the state of Ohio and lived as farmers, while the Shawnee leader Tecumseh took a different course and led the formation of a Confederation of Native Nations and a large scale resistance movement against the United States government in the years prior to the War of 1812. Some of the Indigenous Nations in the South also accepted the "civilization program" and were labeled the "Five Civilized Tribes" by the United States government. Individuals from the Muscogee, Cherokee, Choctaw, Chickasaw, and Seminole Nations emulated white practices, building settler-style towns and plantations, and some Native individuals held even enslaved Black people.

Yet many southern Native American people remained skeptical of "civilization" and joined Tecumseh's movement. Among the Muscogee, a distinct anti-colonial resistance movement called the Red Sticks rose against the United States and the Creek Nation itself during the War of 1812. Ultimately, neither emulation or resistance resulted in a harmonious relationship with the fledgling United States government or kept a stronghold on traditional Tribal Lands, and even those Nations deemed “civilized” by the U.S. were eventually forced from their homes during the Removal Period of the 1830s, known as the Trail of Tears.

United States policies and practices during the Early Republic had profound impacts on the Indigenous Peoples of the Americas, often permanently dividing Nations as individuals within communities made what choices they thought best to preserve their families and their homes. Jefferson’s writings and actions about and towards Indigenous people and Nations demonstrate the complexity of the times, the conflicts of colonization, the hardships endured by many, and presage policies of warfare and cultural genocide enacted by the United States government towards Indigenous peoples. Nevertheless, Native American people fought to hold on to their cultures, languages, and lands. With more than 570 federally recognized Tribal Nations today, and with more than 5 million Native American people living in the United States according to the 2020 Census, Indigenous peoples in the Americas continue to demonstrate their resolve to hold onto their values, their identities, and their ways of life.