As slavery spread and the cruelty of slavery became known among Native Americans, many began to sympathize with Africans and despise the institution of slavery. Many Indian nations began to assist and harbor runaway slaves and intermarry with them, just as Native Americans had done in the Caribbean and in Central and South America as early as 1502. Africans began to forge alliances and close friendships with Native Americans such as the Tuscarora of North Carolina and the group of Native Americans that made up the Iroquois Confederacy. This group included the Mohawk, Cayuga, Oneida, Seneca, and Onondaga, and collectively, along with the Tuscarora, was known as the Six Nations. They grew to mistrust whites and hate the institution of slavery since many of the Tuscarora had fallen victim to this illicit institution after their defeat in the Tuscarora War of 1711-1713.

 As a result, many Iroquois raided frontier plantations, killing whites and allowing Africans to go free or join their nations. Even at the start of the Tuscarora Wai· in 1711, slaves were released by the war­ ring Indians and came to no harm. After the war, from 1717 to 1803, the Tuscarora who remained in North Carolina on a reservation known as Indian Woods began to shelter runaway slaves and sometimes intermarried with them. Many of the Tuscarora and other Iroquois became so mixed that they appeared more African than Indian. Later, as members of the Six Nations were subdued and forced onto reservations, they continued to hide runaway slaves as a part of the Underground Railroad. 

The Meherrin, Nottoway, Delaware, and Powhatan also assisted runaway slaves. Fearful that Indians and slaves might create alliances that would destroy white settlements, whites informed slaves that Indians were their enemy and not to be trusted, causing many slaves to fear them and remain loyal to their masters for protection. Whites also aimed slaves and used them to fight Indians, driving wedges between the two groups as in the Tuscarora War and the Yamasee War of 1715. As well, whites taught Indians to fear Africans and recruited them to serve as slave catchers and slaveholders. Some Indian nations adopted the European type of slavery. 

Most of these nations were bitter enemies of the Tuscarora and the Iroquois Confederacy, and had been even before the arrival of the Europeans. These nations included what became known as the Five Civilized Tribes: the Seminole, Creek, Choctaw, Chickasaw, and Cherokee. Even though these nations accepted many of the practices of European slaveholders, African slavery among them was never as harsh or restrictive as it was among slaveholding whites. For example, many of these Native Ameri­cans intermarried with their African slaves, and the children of slaves were considered free and full members of the nation. The Seminole of Florida became so mixed that, like the Tuscarora and other Iroquois, many of their people be­ came as much African as Indian. The mixing of whites and Indians and Africans and Indians eventually led to civil wars within the Five Civilized Tribes. In these wars, most full-blooded Indians sided with those who were pait African because many of the traditional Native American religions and beliefs did not recognize the superiority of any race over another. On the other hand, many part-white Indians accepted the idea of racial superiority along with Christianity, which was taught to them by whites.