The mission was part of Spain's effort to colonize the Florida Peninsula and to convert the Timucuan and Apalachee Indians to Christianity.

The mission lasted until 1704 when it was evacuated and destroyed to prevent its use by an approaching militia of Creek Indians and South Carolinians.

Today, Mission San Luis operates as a living-history museum with reconstructed Apalachee and Spanish buildings.

In 1528, Pánfilo de Narváez is the first recorded European presence in Apalachee setting up camp south of Anhaica near present-day St. Marks.

In 1625 Apalachees began to send food supplies overland to St. Augustine,[4] the major point of Spanish control over shipping and defense of La Florida.

The Spanish, however, needed the densely populated and extremely fertile Apalachee Province to provide labor and provisions for St. Augustine.

In 1656, Spanish authorities decided to establish their western capital on one of the region's highest hilltops for strategic purposes.

Although the governor planned for further expansion of the garrison and building a regular fort, Apalachee opposition to the project stalled it for well over a generation.

The Apalachee men and women were excellent agriculturists and provided much of the food for San Luis as well as for export to such places as St. Augustine and Havana.

In October 1702, an attempt to turn the blockhouse into a proper fort began after the defeat of a Spanish-Apalachee force on the Flint River.

Unwilling to fight with the Spanish any longer, the Apalachee dispersed to the west, east, and north; some willingly, while many others were enslaved by the English.

Mission San Luis is a living history museum that features an artifact gallery of items recovered from the site, many reconstructed buildings, and third-person interpreters dressed in historical wardrobe.