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Circa 10,000 BC, Paleo-Indians arrived in what is now the southern United States. These southern Native Americans were hunter-gatherers who fed off megafauna before it became extinct after the Pleistocene age. Over a course of several thousand years, the Paleo-Indians gradually developed a rich and diverse agricultural society. Many archaeologists call them the Mississippians because many of the large earthworks they constructed for political and religious reasons still stand throughout the Mississippi and Ohio valleys. Modern descendants of the Mississippians include the tribes Chickasaw and Choctaw. Various other tribes inhabiting Mississippi territory include the Natchez, Yazoo and the Biloxi.

In 1540, Hernando De Soto of Spain became the first known European adventurer to pass through the land that would one day become Mississippi. In April 1699, the French founded the very first European settlement at Fort Maurepas (aka "The Old Biloxi"), built near Ocean Springs by Pierre Le Moyne d'Iberville. When the French established Natchez, also known as Fort Rosalie, on the Mississippi River, it quickly became the main town and trading post in the area. The greater territory towards the west was named "New Louisiana".