The region now known as Louisiana is largely the creation of the Mississippi River; the process of land building still goes on in the Atchafalaya Basin and below New Orleans on the Mississippi Delta. Louisiana was never densely inhabited in prehistoric times, and at no time, probably, did as many as 15,000 Indians live inside the present boundaries of the state. The main relic of prehistoric inhabitants is the great earthwork at Poverty Point, near Marksville, but other Indian mounds are to be found in alluvial and coastal regions.

When white exploration and settlement of North America began, various tribes of Caddo Indians inhabited northwestern Louisiana, and small Tunican-speaking groups lived in the northeast. In the southwest were a number of rather primitive people of the Atakapa group; in south-central Louisiana, the Chitimacha ranged through the marshes and lowlands. Various small Muskogean tribes, related to the Choctaw, lived east of the Mississippi in the "Florida parishes," so called because they were once part of Spanish West Florida. The Natchez Indians, whose main villages were in present-day Mississippi near the city that still bears their name, fought with the French settlers in Louisiana's early history but were exterminated in the process.

Several Spanish explorers sailed along the coast of Louisiana, but Hernando de Soto was probably the first to penetrate the state's present boundaries, in 1541. Almost a century and a half passed before Robert Cavelier, Sieur de la Salle, departing from Canada, reached the mouth of the Mississippi on 9 April 1682, named the land there Louisiana in honor of King Louis XIV, and claimed it for France. La Salle's later attempt at a permanent settlement failed, but in 1699 an expedition headed by Pierre le Moyne, Sieur d'Iberville, made a settlement on Biloxi Bay. In 1714, Louis Juchereau de St. Denis established Natchitoches, the first permanent European settlement in Louisiana; Iberville's brother, the Sieur de Bienville, established New Orleans four years later.

Louisiana did not thrive economically under French rule, either as a royal colony or, from 1712 to 1731, under the proprietorship first of Antoine Crozat and then of John Law's Company of the Indies. On the other hand, French culture was firmly implanted there, and non-French settlers, especially Germans from Switzerland and the Rhineland, were quickly Gallicized. In 1762, on the verge of losing the rest of its North American empire to Great Britain in the French and Indian War, France ceded Louisiana to Spain. Governed by Spaniards, the colony was much more prosperous, although it was a burden on the Spanish treasury. New settlers—Americans, Spaniards, Canary Islanders, and, above all, Acadian refugees from Nova Scotia—added to the population. By 1800 there were about 50,000 inhabitants, a considerable number of them black slaves imported from Africa and the West Indies. The availability of slave labor, Eli Whitney's invention of the cotton gin, and Ètienne de Boré's development of a granulation process for making cane sugar set the stage for future prosperity, though not under Spanish auspices. In 1800, by the secret Treaty of San Ildefonso, Napoleon forced the feeble Spanish government to return Louisiana to France. Three years later, having failed to reestablish French rule and slavery in Haiti, Napoleon sold Louisiana to the US to keep it from falling into the hands of Great Britain.

President Thomas Jefferson concluded what was probably the best real estate deal in history, purchasing 800,000 sq mi (2,100,000 sq km) for $15,000,000 and thus more than doubling the size of the US at a cost of about 3 cents per acre. He made William C. C. Claiborne the governor of the huge new acquisition. The next year, that part of the purchase south of 33°N was separated from the remainder and designated the Territory of Orleans. The people of the territory then began the process of learning self-government, something with which they had had no experience under France and Spain. After the census of 1810 showed that the population had risen to 76,556, the people were authorized by Congress to draw up a state constitution. The constitutional convention met under the presidency of Julian Poydras in a coffeehouse in New Orleans and adopted, with a few changes, the constitution then in effect in Kentucky. In the meantime, in 1810, a revolt against Spain had taken place in West Florida. When the proposed Louisiana constitution reached Washington, Congress added that part of West Florida between the Mississippi and Pearl rivers to the new state, which entered the Union on 30 April 1812.

The key event in the Americanization of Louisiana was the campaign for New Orleans in December 1814 and January 1815, actually fought after the War of 1812 had ended. A force of British veterans under General Sir Edward Pakenham sailed into Lake Borgne and established itself below New Orleans at Chalmette. There they were met by detachments of Creoles, Acadians, blacks, and even Jean Lafitte's pirates, all from Louisiana, as well as Tennesseans, Kentuckians, and Choctaw Indians, with the whole army under the command of Andrew Jackson. After several preliminary battles, the British were bloodily defeated when they launched an all-out assault on Jackson's line.

From 1815 to 1861, Louisiana was one of the most prosperous states in the South, producing sugar and cotton on its rich alluvial lands and grazing hogs and cattle in the wooded hills of the north and on the prairies of the southwest. Yeoman farmers and New Orleans workers far outnumbered the wealthy planters but the planters, whose slaves made up almost half the population, dominated Louisiana politically and economically. When the secession crisis came in 1861, the planters led Louisiana into the Confederacy and, after four bloody years, to total defeat. The state suffered crippling economic losses during the Civil War, but the greatest loss was the lives of tens of thousands of young white men who died in defense of the South, and of thousands of blacks who died seeking and fighting for freedom. Louisiana did not fully recover from this disaster until the mid-20th century.

After the Civil War, radical Republican governments elected by black voters ruled the state, but declining support from the North and fierce resistance from Louisiana whites brought the Reconstruction period to an end. Black people and their few white allies lost control of state government, and most of the former slaves became laborers on sugar plantations or sharecroppers in the cotton fields. There, as the years passed, they were joined by more and more landless whites. In 1898, blacks were disfranchised almost entirely by a new state constitution drawn up primarily for that purpose. This constitution also significantly reduced the number of poorer whites who voted in Louisiana elections.

The vast majority of Louisiana whites—whether hill farmers, Cajuns along the southern rivers and bayous, lumbermen in the yellow pine forests, or workers in New Orleans—were little better off than the black or white sharecroppers. Many economic changes had taken place: rice had become a staple crop on the southwestern prairies, and an oil boom had begun after the turn of the century. But just as before the Civil War, large landowners—combined with New Orleans bankers, businessmen, and politicians—dominated state government, effectively blocking political and social reform. The Populist movement, which succeeded in effecting some change in other southern states, was crushed in Louisiana.

Not until 1928, with the election of Huey P. Long as governor, did the winds of change strike Louisiana; having been so long delayed, they blew with gale force. The years from 1928 through 1960 could well be called the Long Era: three Longs—Huey, who was assassinated in 1935; his brother Earl, who served as governor three times; and Huey's son Russell, who became a powerful US senator—dominated state politics for most of the period. From a backward agricultural state, Louisiana evolved into one of the world's major petrochemical-manufacturing centers. Offshore drilling sent clusters of oil wells 60 mi (97 km) out into the Gulf. The pine lands were reforested, and soybeans provided a new source of income. What had been one of the most parsimonious states became one of the most liberal in welfare spending, care for the aged, highway building, and education. The state could afford these expanding programs because of everincreasing revenues from oil and gas.

In the mid-1980s, a drop in world oil prices rocked Louisiana's economy, hurting the oil exploration and service industries and raising the state's unemployment rate in 1986 to 13%, the highest in the nation. For most of the 1990s, in spite of an increase in service-sector and high-tech jobs, Louisiana had more people living in poverty than any other state. Louisiana had for decades been among the nation's poorest; the percentage of residents living in poverty in 1998 was 19.1%, making it the 2nd-poorest state in the nation. In 1999 it was reported that Louisiana also ranked 2nd-lowest in the nation for its care of children; the report took into account such factors as infant mortality rates, teen pregnancy rates, and children who lived in poverty or lacked health care. Other problems confronting the state at the turn of the century included racial tensions, disposing of toxic wastes from the petrochemical industry, depletion of oil and gas resources, and the ongoing struggle to institute good government.

The announcement in February 1985 by Russell B. Long, senator since 1948, that he would not seek reelection, and the indictment of former Governor Edwin W. Edwards by a federal grand jury on conspiracy charges during the same month, caused turmoil in Louisiana's political arena. Edwards was defeated in 1987 by Buddy Roemer, a young, well-educated Republican who promised to clean up government. In 1989, racial tensions surfaced when white supremacist David Duke, running as a Republican, narrowly won a seat in the Louisiana state legislature. Duke later ran unsuccessfully for the US Senate and for governor, but his runs for office had raised concerns about the level of frustration of many white voters. In 1995 gubernatorial candidate Murphy "Mike" Foster, Republican, promised more Roemer-like reforms. As he faced reelection four years later, some analysts said the Bayou State had made progress in building a trustworthy and responsive government. Nevertheless, Foster was criticized for favoring the oil industry and being soft on big gambling. He still managed to win another term, claiming 64% of the vote.

In 1999, Governor Murphy J. (Mike) Foster became the first Republican governor in Louisiana history to be reelected. He offered the New Orleans Saints professional football team $186.5 million in subsidies in 2002 to keep the team from moving out of the state. Foster maintained the football team had a salutary effect on Louisiana's economy.