The first European expedition into the territory that became Mississippi was that of Hernando de Soto, who passed through in 1540. The first settlement was that of Ocean Springs (or Old Biloxi), settled by Pierre Le Moyne d'Iberville in 1699. In 1716, Natchez was founded on the Mississippi River (as Fort Rosalie); it became the dominant town and trading post of the area. After spending some time under Spanish, British, and French nominal jurisdiction, the Mississippi area was deeded to the British after the French and Indian War under the terms of the Treaty of Paris.

The Mississippi Territory was organized on April 7, 1798, from territory ceded by Georgia and South Carolina; it was later twice expanded to include disputed territory claimed by both the U.S. and Spain. Land was purchased (generally through unequal treaties) from Native American tribes from 1800 to about 1830.

When cotton was king during the 1850s, Mississippi plantation owners—especially those of the Delta and Black Belt regions—became increasingly wealthy due to the high fertility of the soil and the high price of cotton on the international market. The severe wealth imbalances and the necessity of large-scale slave populations to sustain such income played a heavy role in both state politics and in the support for secession. Mississippi was the second state to secede from the Union as one of the Confederate States of America on January 9, 1861. During the Civil War the Confederate States were defeated. Under the terms of Reconstruction, Mississippi was readmitted to the Union on February 23, 1870.

Mississippi was considered to typify the Deep South during the era of Jim Crow. A series of increasingly restrictive racial segregation laws enacted during the first part of the 20th century resulted in the emigration of almost half a million people, three-quarters of them black, in the 1940s. However, at the same time, Mississippi became a center of rich, quintessentially American music traditions: gospel music, country music, jazz music, blues, and rock and roll all were invented, promulgated, or heavily developed by Mississippi musicians. Mississippi was also noted for its authors in the early twentieth century, especially William Faulkner and Tennessee Williams.

Mississippi was a focus of the American Civil Rights Movement. Most white Mississippians, through their politicians and involvement in the White Citizens' Council movement, and the violent tactics of its Ku Klux Klan members and sympathizers gave Mississippi a reputation as a reactionary state during the 1960s. The only nuclear weapons ever detonated east of the Mississippi were near Hattiesberg.

Perhaps symbolic of its reactionary reputation, the state was the last to repeal prohibition and to (symbolically) ratify the Thirteenth Amendment, which abolished slavery, in 1966 and 1995 respectively--though these amendments were already legally in effect in Mississippi, as in the rest of the U.S.

Legislative authority resides in the state legislature, composed of the Senate and House of Representatives. The lieutenant governor presides over the Senate, while the House of Representatives selects their own Speaker. The state constitution permits the legislature to establish by law the number of senators and representatives, up to a maximum of 52 senators and 122 representatives. Current state law sets the number of senators at 52 and representatives at 122. The term of office for senators and representatives is four years.

Supreme judicial authority rests with the state Supreme Court, which has statewide authority. In addition, there is a statewide Court of Appeals, as well as Circuit Courts, Chancery Courts and Justice Courts, which have more limited geographical jurisdiction. The nine judges of the Supreme Court are elected from three districts (three judges per district) by the state's citizens in non-partisan elections to eight-year staggered terms. The ten judges of the Court of Appeals are elected from five districts (two judges per district) for eight-year staggered terms. Judges for the smaller courts are elected to four-year terms by the state's citizens who live within that court's jurisdiction.

Mississippi is one of the most conservative states in the US, and with religion often playing a large role in citizens' political views. Liquor laws are particularly strict and variable from jurisdiction to jurisdiction. Liquor sales are frequently banned on Sunday. Many counties allow no alcoholic beverage sales ("dry"), while others allow beer but not liquor, or liquor but not beer. Some allow beer sales, but only if it is warm. These laws make roads leading from dry to wet counties hazardous on weekend evenings as inebriated residents return home. In 2004, 86% of voters amended the state constitution to ban any legal rights for same sex couples- the highest level of support any such initiative has received in the United States.

Mississippi's rank as one of the poorest states can be traced to the Civil War. Before the Civil War, Mississippi was the fifth-wealthiest state in the nation. Slaves were then counted as valuable property and, in Mississippi, more than half the population was enslaved; in non-slave states, human capital was not included in estimates of wealth. Further, Mississippi's antebellum wealth rank should not be compared with today's GDP rank, which is an estimate of income; wealth and income are separate concepts. The war cost the state 30,000 men. Plantation owners who survived the war were virtually bankrupted by the emancipation of slaves and Union troops left widespread destruction in their wake.

A decision in 1990 to legalize casino gambling along the Mississippi River and the Gulf Coast has led to economic gains for the state. However, an estimated $500,000 per day in tax revenue was lost following Hurricane Katrina's severe damage to several coastal casinos in August 2005. Gambling towns in Mississippi include the Gulf Coast towns of Bay Saint Louis, Gulfport and Biloxi, and the Mississippi River towns of Tunica, Greenville, Vicksburg and Natchez. Before Hurricane Katrina struck the Gulf Coast, Mississippi was the second largest gambling state in the Union, ahead of New Jersey and behind Nevada.

On October 17, 2005, Governor Haley Barbour signed a bill into law that now allows casinos in Hancock and Harrison counties to rebuild on land (but within 800 feet of the water). The only exception is in Harrison County, where the new law states that casinos can be built to the southern boundary of U.S. Route 90.