The Spanish conquistador Hernando de Soto crossed what is now Mississippi in 1540-41. In the late 1600's French explorers from Canada reached the lower Mississippi Valley and claimed it for France under the name of Louisiana. Sieur d'Iberville established the first French settlement at Old Biloxi (now Ocean Springs) in 1699.

Under Sieur de Bienville, Iberville's brother, the French founded settlements at Mobile (in 1702, at a site north of the present-day city) and Natchez (1716). When the capital of the region called Louisiana was established at New Orleans in 1722, there were about 3,000 French and 2,000 blacks in the colony. The Natchez Indians, a small tribe, were being crowded off their land. In 1729 they massacred the settlers at Fort Rosalie (Natchez), and in reprisal were driven from the region.