In 1513 Ponce de Leon set out to explore the east and west coasts of Florida. During this exploration, he returned to the Charlotte Harbor area to establish a colony. During the colonization period, the Calusa Indians attacked Ponce de Leon’s settlement. Ponce de Leon was wounded in the thigh by an arrow, resulting in a bout with gangrene that would eventually claim his life in Havana. Several years later, the American mainland was opened for European settlement by the Hernando DeSoto expedition of 1539-42.
According to various historical documents, Pedro Menendez D'Aviles built a mission-fort named San Antonio somewhere in the Charlotte Harbor region following his establishment of the first American colony at St. Augustine, Florida, in 1565. After two intense years of struggle between the Spaniards and the Calusa, Menendez abandoned his project and attempted to restrain the unpredictable Indians of southern Florida.