The Jocassee gorges area was once home to the part of the Cherokee Nation; it now lies 300 feet beneath the surface of the lake, near the Toxaway River. Nearby Keowee Town was a major hub in the Cherokee Path that connected Cherokee towns and villages throughout the area. Early 18th century traders delivered as many as 200,000 deerskins annually to Charleston, South Carolina and local Indians became well supplied with European firearms, ammunition, tools and clothing as a result. However, mounting discord between Europeans and Cherokees led to war in 1759. In 1785, General Andrew Pickens hosted a large gathering of Indian chiefs leading to a treaty that gave all of the Jocassee gorges area, with the exception of northern Oconee County, to the United States; the Oconee mountains were not ceded until 1815. European settlers, mostly of Scotch and Irish descent, came from Virginia and Pennsylvania as well as from Charleston. Land grants in the Jocassee area go back to 1791.
A rare wildflower, the Oconee bell, native to only a few counties in the Blue Ridge area, was discovered in the area in 1788 by French botanist Andre Michaux. The creation of Lake Jocassee is said to have caused the destruction of the heart of the species' range. More recently, biologists have documented the occurrence of a number of rare, threatened and endangered species. The Eastatoee Gorge Heritage Preserve was transferred from Duke Power Company to the South Carolina Department of Natural Resources in 1979 due to the extremely diverse flora occurring there.