In the winter of 1540 Hernando de Soto led a large expedition into Mississippi and wintered along the Pontotoc River. In the following spring he reached the Mississippi River, but, because he found no gold or silver in the region, Spanish explorers directed their efforts elsewhere.

Nearly 130 years later a small group of French Canadians sailed down the Mississippi River and immediately realized its commercial and strategic importance. In 1699 a French expedition led by Pierre le Moyne d'Iberville established France's claim to the lower Mississippi valley. French settlements were soon established at Fort Maurepas, Mobile, Biloxi, Fort Rosalie, and New Orleans. 

Following the French and Indian War, which ended in 1763, France ceded its possessions in the lower Mississippi valley, except New Orleans, to Great Britain, which also gained possession of Spanish Florida and divided that territory into two colonies. One of those was West Florida, which included the area between the Apalachicola and Mississippi rivers. The original northern boundary of West Florida was the 31 parallel, but it was extended in 1764 to the 3228' parallel. Fort Rosalie was renamed Fort Panmure, and the Natchez District was established as a subdivision of West Florida. Natchez flourished during the early 1770s. After the outbreak of the U.S. War of Independence, Spain regained possession of Florida and occupied Natchez. The Treaty of Paris of 1783 fixed the 31 parallel as the boundary between Spanish Florida and the United States, but Spain continued to occupy Natchez until the dispute was settled in 1798.

The original Mississippi Territory created by the U.S. Congress in1798 was a strip of land extending about 100 miles north to south and from the Mississippi River to the Chattahoochee on the Georgia border. The territory was increased in 1804 and 1812 to reach from Tennessee to the Gulf. In 1817 the western part achieved statehood as Mississippi (the eastern part became the state of Alabama in 1819). Natchez, the first territorial capital, was replaced in 1802 by nearby Washington, which in turn was replaced by Jackson in 1822. 

 The 1820s and '30s were marked by the decline of the Jeffersonian Republicans, the ascendancy of the Jacksonian Democrats, and the removal of the Indians to Oklahoma. They were the days of steamboats, land speculation, and the growth of a plantation-based cotton economy, with its concomitant slave population. Slave owning, however, was not common among the small landowners, who became more numerous than the large planters but who had little influence on public affairs for many years.
 Sectionalism in both North and South had been growing for some time. Its ill feelings gradually became dominated in both North and South by slavery. In January 1861, a convention adopted an ordinance of secession, and within a year the state was in the midst of war. The people suffered much privation, and the land underwent great devastation; by 1865 the state was in economic ruin.

For 25 years following the Civil War, Mississippi's former slaves and their former owners grappled with the political, social, and economic consequences of emancipation. The white minority could not or would not accept a biracial society based on equality of opportunity. In 1890 the ruling elite adopted a constitution that established a caste system of racial segregation and an economic order that kept blacks in a position of dependency.
 Mississippians hoped to find economic salvation in the coming of industry and the railroads, but the hope was only partially realized. Emancipation had made the former slaves free to go where they wished, but most remained and eventually were absorbed into the tenant-farming system. The continued economic interdependence of the two races kept intact many of the customs and social systems that had developed before the war. The constitution of 1890 effectively disfranchised most of the black population.