Natchitoches was established in 1714 by Louis Juchereau de St. Denis. It is the oldest permanent settlement within the borders of the 1803 Louisiana Purchase. Natchitoches was founded as a French outpost on the Red River for trade with Spanish-controlled Mexico, with the French presence beginning as early as 1699. The settlement's site was established near a village of Natchitoches Indians which give the city its name.

After the Louisiana Purchase, Natchitoches experienced a population boom, and several plantations were built along the Red River. However, the course of the river shifted, bypassing Natchitoches and cutting off its lucrative connection with the Mississippi River. A 33-mile (53 km) lake was left in the river's previous location.

It became known as Cane River Lake. The lake runs through the city’s downtown historic district and Plantation Country. It serves as the spring break training location for numerous crew teams, such as Kansas State University, University of Kansas, Wichita State University, Murray State University and Washington University.

Natchitoches was the site of the 1973 plane crash that claimed singer Jim Croce's life. Croce had just performed a concert on campus for Northwestern State University students at Prather Coliseum.