During the 1770s, European frontiersmen established the "Nolichucky settlements" along the river in modern Greene County, Tennessee, in what was then part of Cherokee territory.
The turn of the century brought trains hauling passengers (until 1955) and mostly coal on the Clinchfield Railroad (now operated by CSX), which still runs alongside the river through the gorge with bridged crossings at Unaka Springs (Erwin, Tennessee) and Poplar, North Carolina.