Little is known of the Indian cultures existing in the Okefenokee region prior to the explorations of Hernando de Soto in the early 16th century. There is evidence to indicate that many small groups of people lived around the region. According to research by the Okefenokee National Wildlife Refuge office, Indians inhabited Okefenokee Swamp as early as 2500 B.C. Tribes of the Depford Culture, the Swift Creek Culture and the Weeden Island Culture occupied sites within the Okefenokee.

De Soto's raid into Georgia (around 1540) spread disease throughout these communities, causing the collapse of most existing cultures. As white settlers moved into the country, massive migrations of various Indian tribes sought the Okefenokee as a safe haven. The influence of the language of the Creek confederacy (mushkogee) is memorialized across the southern United States by its use for the names of many current towns and rivers.

The last Native Americans to seek sanctuary in the swamp were the Seminoles. It is believed the famous Seminole warrior, Osceola, spent time in the Okefenokee as a child during the southern migration of the Seminole people. An armed militia led by General Charles R. Floyd ended the age of the Indian in the Okefenokee by driving the Seminoles into Florida. Possibly, these impressions gave a young Osceola the strength and determination to resist American domination to the end.

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