The indigenous people of the Everglades region arrived in the Florida peninsula of what is now the United States approximately 14,000 to 15,000 years ago, probably following large game. The Paleo-Indians found an arid landscape that supported plants and animals adapted to prairie and xeric scrub conditions. Large animals became extinct in Florida around 11,000 years ago. Climate changes 6,500 years ago brought a wetter landscape. The Paleo-Indians slowly adapted to the new conditions. Archaeologists call the cultures that resulted from the adaptations Archaic peoples. They were better suited for environmental changes than their ancestors, and created many tools with the resources they had. Approximately 5,000 years ago, the climate shifted again to cause the regular flooding from Lake Okeechobee that gave rise to the Everglades ecosystems.

From the Archaic peoples, two major tribes emerged in the area: the Calusa and the Tequesta, who were of Taíno origin, an Arawak people, originating from the Caribbean and South America. The earliest written descriptions of these people come from Spanish explorers who sought to convert and conquer them. Although they lived in complex societies, little evidence of their existence remains today. The Calusa were more powerful in number and political structure. Their territory was centered on modern-day Ft. Myers, and extended as far north as Tampa, as far east as Lake Okeechobee, and as far south as the Keys. The Tequesta lived on the southeastern coast of the Florida peninsula around what is today Biscayne Bay and the Miami River. Both societies were well adapted to live in the various ecosystems of the Everglades regions. They often traveled through the heart of the Everglades, though they rarely lived within it.