The Calusa resisted all attempts to convert them to Christianity, remaining true to their own beliefs. They still lived in their homeland and exerted influence on neighboring polities as late as 1698, long after the ravages of European diseases, forced labor, and warfare had devastated North Florida populations. Calusa population had been reduced to perhaps 2,000 by that time.

By 1711, the Calusa had been overrun by armed Creek and Yamasee Indians from present-day Georgia and South Carolina, who sold the south Florida natives to the English as slaves. These northern intruders had been themselves displaced by slave raiding, colonization, and military activities of the English, French, and Spanish. European-introduced diseases, slavery, and war finally took their toll on the Calusa. Following 1711, remnants of Calusa and other groups lived in the Florida Keys, under continuing pressure from Creeks and Yamasees.

Spaniards living in Cuba tried belatedly to rescue some of the beleaguered Indians, but most of those transported died quickly of diseases. A few remnant Indian groups living in the Florida Keys were later contacted by Jesuits in 1743. Although the Calusa had successfully resisted conquest for over 200 years, ultimately they fell victim to political struggles that originated in European colonialism. By the 1750s their culture had been essentially erased from Florida.