In 1839, this was an unimproved large path, part of what became known as the Trail of Tears as the Cherokee people were forcibly removed from their homelands in this region to west of the Mississippi River and Indian Territory.

The river rises near the border of Georgia and North Carolina, close to the Southern Nantahala Wilderness and the Appalachian Trail.

[6] The river runs through a narrow and steep gorge where in some areas the sun reaches the ground only when it is directly overhead during the middle of the day.

Commercial rafting began in 1972 when the Nantahala Outdoor Center opened, leading to thousands of paddlers annually running the river.

The river is frequently used for competitions, clinics, and practices held by the US Men's and US Youth National Fly Fishing teams.

Most recently, the Nantahala played host to the 2015 US Youth National Fly Fishing Championship and the 2015 Men's Southeast Regional, with sessions held on the Upper and Lower sections, as well as the Raven's Fork on the nearby Cherokee Indian Reservation.

From late spring to early fall Duke Energy follows a regular release schedule[8] to help support commercial rafting.

The uppermost section just below Whiteoak Falls is known as the Nantahala Cascades and is an extremely steep and challenging whitewater route.

This section of the channel is narrow and features several Class III+ to V rapids including "The Horns of God", "Big Kahuna", and "Chinese Feet."