Before European colonization, the Coastal Plains were home to several Native American cultures, most notably the Mississippian and Creek peoples.

The Mississippian culture, known for its advanced agricultural practices, built large earthen mounds and established complex regional trade networks. They cultivated crops such as maize, beans, and squash, which supported their growing populations. The Creek, or Muscogee, was also significant in the Coastal Plains, known for its matrilineal social structures and rich cultural traditions. Both cultures played essential roles in the region's history, leaving lasting legacies in agriculture, trade, and social organization, significantly influencing the area's development before European contact.