Indigenous people lived in this area for thousands of years. Due to warfare and exposure to infectious diseases after European contact, native tribes became depopulated. In the eighteenth century, when the area was under Spanish rule, Native American peoples of Creek and other tribes migrated into present-day Florida from Georgia. Africans and African Americans who escaped from slavery and shipwrecks also migrated to the area, where they created maroon communities. Some were given freedom by the Spanish in exchange for serving with their militias. Gradually the Seminole nation formed out of these multi-ethnic people. Some African-descended people set up communities near the Seminole and became known as Black Seminole. In the nineteenth century, most of the Seminole and many blacks were removed to Indian Territory after the Seminole Wars, a result of pressure from increasing Anglo-American settlement.
Glades County was created in 1921. It was named for the Florida Everglades.
Glades County sponsors one of Florida's oldest recurring festivals. Chalo Nitka Festival is a celebration of local history and culture, similar to a county fair. The festival also draws attention to the long and friendly relationship between the local Seminole groups and Glades County settlers. Brighton Seminole Indian Reservation is located in the county.