Waccasassa Bay is rich with cultural history dating from pre-Columbian to early pioneers to the Civil War to modern day timber harvesting. Florida’s early pioneers homesteaded and hunted deer, turkey and bear here. They cut timber and "cow hunted" as well. Yet their activities did not greatly alter the wilderness character of the land. The hammock played a major role in the development of Cedar Key, providing cedar for the pencil factories and palm trees for the fiber factory. Remnants of the boilers once used in the production of brushes and brooms made from the sable palm fibers can be found within the boundaries of the preserve. Another remnant of bygone industry is Salt Island, named for salt kettles found there which were used to extract salt from salt water during the Civil War. Numerous homesites of early settlers as well as Indian sites and artifacts have been found in the preserve.

Disturbance of these sites and the removal of any artifacts is prohibited.