During the 1600s and 1700s, several European powers established outposts for commerce, defence, and settlement in North America. Spain, France, and Great Britain were among the forces involved in establishing colonies in North America. French explorers used the Great Lakes and the Mississippi River to penetrate the continent, intending to develop strategic points for collecting raw materials and making the colonies self-sufficient. Great Britain established its tobacco-growing colonies along the Atlantic coast. At the same time, Spain searched for precious metals along the Gulf of Mexico, the Pacific coast, and throughout Central and South America. The European powers ultimately turned to importing enslaved Africans to provide labour for their ambitious colonial plans.

This imperial struggle in North America led to the French and Indian War in 1754-1763, which positioned France against Great Britain. Each side had strategic alliances with different American Indian tribes. This war resulted in British control of North America east of the Mississippi River, except for New Orleans.

France was the first of the three great European powers to recognise and appreciate the strategic importance of Natchez. French explorers crossed the Great Lakes and followed smaller streams into the Mississippi River. In 1673, Father Jacques Marquette and Louis Joliet descended as far south as the Arkansas River. In 1682, René-Robert Cavalier, Sieur de La Salle, discovered the point where the Mississippi River emptied into the Gulf of Mexico and laid claim to the entire Mississippi Valley in the name of France.

La Salle became the first Frenchman to encounter the Natchez Indians and declare them an ally. Between 1699 and 1702, the Natchez welcomed the explorer Pierre Le Moyne Albertville and allowed a French missionary to settle among them. The Natchez tribe of American Indians lived in the Natchez bluffs area along the lower Mississippi River valley. Archaeological evidence shows them in the region as far back as 700 CE. The Natchez had a complex and unusual social system with a stable matrilineal kinship society. Their last main political and ceremonial centre is preserved at the Grand Village of the Natchez Indians' mound site.

During the 1710s and the 1720s, the French presence and settlement in the Natchez territory increased from a handful of traders to hundreds of settlers and enslaved Africans. At first, the Natchez welcomed the French settlers, but growing tensions over the confiscation of land resulted in four wars between 1716 and 1729 and the removal of the Natchez from this area. The French introduced the use of kidnapped and enslaved Africans as a labour force in the Natchez District by 1719. The international slave trade was established in the 17th century when trading ships set sail from Europe with cargo destined for Western Africa. There, the goods would be traded for captured people to be sold into slavery. Once their ships were complete with human cargo, European traders would set sail for the Americas.

At first, the French envisioned a fur-trading economy in the Lower Mississippi River Valley. However, the newly established French Company of the Indies introduced tobacco as a cash crop in an attempt to replicate the financial success of the British in Virginia. The company quickly began to import large numbers of enslaved Africans to create a plantation economy. The Natchez Massacre in 1729 brought an end to those dreams. Not until the late 1700s, after marginal growth during the British and Spanish reigns, would the plantation slave-based economy begin to emerge. In 1795, Eli Whitney invented the cotton gin, and the Natchez District quickly became the centre of the tragic system of American chattel slavery.