First explored for Spain by Hernando de Soto, who discovered the Mississippi River in 1540, the region was later claimed by France. In 1699, a French group under Sieur d'Iberville established the first permanent settlement near present-day Ocean Springs.

Great Britain took over the area in 1763 after the French and Indian Wars, ceding it to the U.S. in 1783 after the Revolution. Spain did not relinquish its claims until 1798, and in 1810 the U.S. annexed West Florida from Spain, including what is now southern Mississippi.

The Civil War disrupted the profitable economy, and much of the economic growth after the War is attributable to freed slaves who cleared land for farming and development. They were able to work to ownership of the land, and at its peak a majority of farms were owned by black farmers. However, natural challenges, falling cotton prices, and racial enmity led to many of those farmers losing their farms by the 1930s and 1940s. 

For a little more than one hundred years, from shortly after the state's founding through the Great Depression, cotton was the undisputed king of Mississippi's largely agrarian economy. Today, agriculture continues as a major segment of the state's economy. For almost four decades soybeans occupied the most acreage, while cotton remained the largest cash crop. In 2001, however, more acres of cotton were planted than soybeans, and Mississippi jumped to second in the nation in cotton production (exceeded only by Texas).

The state abounds in historical landmarks and is the home of the Vicksburg National Military Park. Other National Park Service areas are Brices Cross Roads National Battlefield Site, Tupelo National Battlefield, and part of Natchez Trace National Parkway. Pre-Civil War mansions are the special pride of Natchez, Oxford, Columbus, Vicksburg, and Jackson.