Prior to colonial settlement, the area comprising Louisa County was occupied by several indigenous peoples including the Tutelo, the Monacan, and the Manahoac peoples, who eventually fled to join the Cayuga Iroquois (Haudenosaunee) people in New York state under pressure from English settlers.
By 1701, the Saponi and allied tribes, often collectively referred to as "Saponi" or "Tutelo," had begun moving to the location of present-day Salisbury, North Carolina to distance themselves from the colonial frontier.