In pre-Columbian times, the area that is today the state of Louisiana was home to many Native American peoples. These included the Atakapa, Chitmacha, Bayougoula, Houma, Avoyel, Tunica and Caddo.

The first Europeans to visit the region were Spanish explorers in the 16th century. In 1528, Panfilo de Narvaez's expedition visited the mouth of the Mississippi River, and in 1541, Hernando de Soto crossed the region. The French began arriving in the late 17th century and quickly established settlements. Robert Cavelier de La Salle named the region "Louisiana" in honor of the French King, Louis XIV, in 1682. And a settlement, Fort Maurepas, was established in 1699 (at what is now Ocean Springs, Mississippi, near Biloxi.

The French colony of Louisiana contained land on both sides of the Mississippi River and extended all the way to Canada, including all or part of the following present-day states: Louisiana, Mississippi, Arkansas, Oklahoma, Missouri, Nebraska, Kansas, Iowa, Illinois, Michigan, Wisconsin, Minnesota, South Dakota and North Dakota.

Following the Seven Years' War (generally known in the US as the "French and Indian War"), control of most of the territory east of the Mississippi River, with the exception of the area around New Orleans passed to the British, and the rest of French Louisiana became a colony of Spain. During this period, French-speaking refugees from Acadia (French colonies in Canada and New England) arrived in what is today Southwest Louisiana, their descendants eventually becoming known as the Cajun people.

In 1800, France reacquired Louisiana from Spain in a secret treaty, however three years, in 1803, the territory was sold to the United States, in the Louisiana Purchase.

The United States divided Louisiana into two parts; the Orleans Territory (which was to become the state of Louisiana in 1812), and the District of Louisiana (which was all the rest of the land acquired in the Louisiana Purchase).

A boundary dispute then arose between the US and Spain over West Florida, with the Spanish insisting that this region had not been sold back to France in 1800. However, in the meantime, British settlers have moved into the area, and rebelled against Spain in 1810 forming the short-lived West Florida Republic, which was later annexed to the United States (eventually becoming Louisiana's Florida Parishes) by Presidential proclamation.