The shores of Tampa Bay have been inhabited for thousands of years. Various cultures developed in the area, with the Weeden Island culture being the most prevalent 2000 years ago.
At the time of European contact in the early 16th century, several chiefdoms of the Safety Harbor culture dominated the area. The most well-known of these chiefdoms were the Tocobaga, whose principal town was at the northern end of Old Tampa Bay, and the Calusa, who lived to the south.
Expeditions led by Pánfilo de Narváez and Hernando de Soto landed near Tampa, but neither conquistador stayed long. The indigenous cultures of the Tampa Bay area had collapsed by around 1600, leaving the area largely depopulated.
In the mid-18th century, events in the American colonies and the early United States drove the Seminole people into northern Florida. They did not move into central Florida until after the United States gained control of Florida in 1821.