The Greenbrier River begins at a high elevation in Pocahontas County and flows 162 miles south and west to join the New River at Hinton. Its path is straight for much of its length because it flows along the border between two different geologic regions: the folded Ridge and Valley and the flatter Appalachian Plateau.

The region's limestone soil is very rich, making the Greenbrier Valley excellent farmland from the earliest European settlements to today. Settlers followed Indian trails, like the Seneca, to reach the valley. During the Civil War, the area saw a good bit of fighting, including the Battle of Droop Mountain in 1863.

The river itself was used only for short periods to float timber down to sawmills. After the forests were cut down, major floods became a problem, including disastrous ones in 1877, 1985, 1996, and 2016. The floods have been especially controversial because the Greenbrier remains the last major river in West Virginia to flow its entire length without any man-made dams or impediments; however, this also has made it a popular spot for fishing, swimming, and other recreation.