The Santee Experimental Forest is a 6,100-acre research facility located within the Francis Marion National Forest, SC. Situated within the Huger Creek watershed in the headwaters of the East Branch of the Cooper River, the Santee Experimental Forest supports research in forest ecology, silviculture, prescribed fire, forest hydrology, ecosystem restoration, and wildlife management. Although the Santee Experimental Forest came into existence based on early 20th-century timber practices and the resulting needs for information on sustainable forestry practices, its boundaries have supported a wide array of human development for over 300 years. This paper provides an overarching history of land use on the Forest and regional perspectives. This environmental history also explains how Huger Creek ecosystems influenced people's alteration the landscape. Livestock, naval stores, rice, cotton, and truck farming represent human production on the land from the colonial to postbellum eras. Logging and forest management replaced the earlier industries as political, social, and economic factors evolved at the turn of the 20th century. By documenting human development upon the land, a clear understanding of changing landscapes and ecological succession provides needed context for the Santee Experimental Forest's scope and mission. This environmental history also provides the basis for considering the influences of past uses on the delivery of ecosystem goods and services in a restored forest landscape.