In 1597 the chiefs of the Potano and other Western Timucuan tribes had pledged allegiance to the governor of la Florida, Gonzalo Méndez de Canço, in St. Augustine.

A fourth mission in the area, San Buenaventura de Potano was established a short time later.

[5] At least one of the cattle ranches operated by the Spanish in Florida in the later part of the 17th century was located near San Francisco de Potano.

Starting the 1680s and accelerating after 1700 during Queen Anne's War, English settlers from the Province of Carolina and various Indian tribes allied with them repeatedly attacked Spanish missions in Florida.

The remaining Indians at San Francisco de Potano moved east of the St. Johns River in 1706, abandoning the mission 100 years after it was established.