The land which became St. Landry Parish was inhabited since at least 10,500 B.C., as deduced from excavations of three prehistoric dwelling sites. By the 15th century, the Appalousa Indians settled in the area situated between Atchafalaya River and Sabine River (at the border of Texas-Louisiana). The Appalousa were a warlike tribe, preying on their neighbors to keep their own territory.
The first European recorded in the Appalousa territory was the French trader Michel de Birotte. He came in 1690 and negotiated with the Appalousa nation. Nine years later in 1699, France named Louisiana as a colony and defined the land occupied by the Appalousa as the Opelousas Territory. The area south of the Opelousas Territory between the Atchafalaya River, the Gulf of Mexico and Bayou Nezpique, occupied by the Attakapas Indians (Eastern Atakapa), was named Attakapas Territory.
In 1720 France established the Opelousas Post slightly north of the contemporary city of Opelousas. It was a major trading organization for the developing area. In addition France established the Attakapas Post (near the present St Martinville) in the Attakapas Territory. France gave land grants to soldiers and settlers to encourage development. Most settlers were French immigrants. Tradition holds that Jean Joseph LeKintrek and Joseph Blainpain, who had formed a partnership to trade with the Opelousas Indians, came in the early 1740s. They brought with them three enslaved Africans, the first Africans to live in the area.
Some natives sold pieces of land to the settlers. After the Eastern Attakapas Chief Kinemo sold all the land between Vermilion River and Bayou Teche to the Frenchman Gabriel Fuselier de la Claire in 1760, the Opelousas exterminated the Attakapas (Eastern Atakapa).
France ceded Louisiana and its territories to Spain in 1762. Under Spanish rule, Opelousas Post was established as the center of government for Southwest Louisiana. By 1769 about 100 families were living in Opelousas Post. Between 1780 and 1820, the first settlers were joined by others coming from the Attakapas Territory, from the Pointe Coupée Territory, and east from the Atchafalaya River area. They were joined by immigrants from the French West Indies, who left after Haiti/St. Domingue became independent in a revolution by the slaves and free people of color. Most of the new settlers were French, Spaniards, French Creoles, Spanish Creoles, Africans and African Americans.
The group coming from Attakapas Post included many Acadians. These Acadians were French who migrated from Nova Scotia in 1763, after expulsion by the English in the aftermath of the defeat of France in the Seven Years' War (known in North America as the French and Indian Wars). They were led by Jean-Jacques Blaise d'Abbadie. Jean Jacques Blaise d'Abbadie was Governor of the territory from 1763 to 1765. The French community built St Landry Catholic Church in 1774, dedicated to St. Landry, the Bishop of Paris in the 7th century.
On April 10, 1805, after the US acquired the Louisiana Purchase in 1803, the post was named as the town of Opelousas and established as the seat of St Landry Parish.
The United States gained control of the territory in 1803 through the Louisiana Purchase. Americans from the South and other parts of the United States began to migrate to the area, marking the arrival of the first large English-speaking population and the introduction of the need for more general use of English.
St. Landry Parish was officially established on April 10, 1805 by a legislative act, becoming the largest parish in the Louisiana state. The new parish was named after the Catholic Church located near the Opelousas Post. The church had been named in honor of St. Landry, the Bishop of Paris in 650. The parish's boundaries encompassed about half the land of the Opelousas Territory, between the Atchafalaya River and Sabine River, between Rapides Parish and Vernon Parish, and Lafayette and St. Martin Parishes. Since then, the area of the parish has decreased, as six additional parishes have been created from its territory. These include Calcasieu, Acadia, Evangeline, Jeff Davis, Beauregard, and Allen.
In 1821 the second educational institution west of the Mississippi was founded in Grand Coteau. In this community south of Opelousas is the Academy of the Sacred Heart, a private Catholic school founded by the French Creole community.
The city of Opelousas has been the seat of government for the St Landry Parish since its formation. After Baton Rouge fell to the Union troops during the Civil War in 1862, Opelousas became the state capital for nine months. The capital was moved again in 1863, this time to Shreveport when Union troops occupied Opelousas.
The parish has a total area of 939 square miles, of which 929 square miles is land and 10 square miles (1.08%) is water. The population recorded in the 1900 Federal Census was 52,906. The 2010 census recorded 83,384 residents in the Parish.
Neigboring parishes are Avoyelles Parish (north), Pointe Coupee Parish (east), St. Martin Parish (southeast), Lafayette Parish (south), Acadia Parish (southwest), and Evangeline Parish (northwest). Communities in the parish include Eunice, Opelousas, Arnaudville, Cankton, Grand Coteau, Krotz Springs, Leonville, Melville, Palmetto, Port Barre, Sunset, and Washington.