The Greenbrier River rises in two forks in the high mountains at the northern end of Pocahontas County, at elevations exceeding 3,600 feet. The East and West forks join at Durbin, and from there the river flows in a generally southwesterly direction through Pocahontas and Greenbrier counties before joining the New River at Hinton in Summers County. From Durbin to Hinton, the Greenbrier flows 162 miles. The river's drainage area of 1,656 square miles includes most of Pocahontas and Greenbrier counties, and parts of Monroe and Summers. The major tributaries are Deer Creek, Knapps Creek, Spring Creek, Anthony Creek, Howard Creek, Second Creek, and Muddy Creek.

The Greenbrier's relatively straight course through Pocahontas and most of Greenbrier County is due to its location along the boundary between the folded rock of the Ridge and Valley geologic province on the east and the flat-lying rock of the Appalachian Plateau to the west. The lower section of the river, below Ronceverte, swings to the west onto the Plateau and develops a more meandering course. The limestone soils of the Greenbrier Valley have made it a region of fine farms from the days of the first European settlers to the present.

Indians are believed not to have been permanent residents of the valley, but users of the area on a seasonal basis. European explorers, hunters, and trappers were in the valley by the late 1600s and early 1700s, and may have included both French and English. Land grants on the Greenbrier watershed were made in the 1740s and settlement was under way by the 1750s.

As they moved west, settlers followed the trails used by the natives. Several trails passed through the Greenbrier Valley, with the Seneca Trail perhaps the best known today. During the Civil War, the movement of troops brought the horrors of war to the valley. The 1863 Battle of Droop Mountain was fought within sight of the river.

The Chesapeake & Ohio Railway (now CSX), constructed after the Civil War, parallels the lower section of the river on its route from Virginia to the west. The railroad's former Greenbrier Division, now the Greenbrier River Trail, provided rail transportation to the upper part of the Greenbrier Valley.

The shallow river itself has been used as a means of transportation in only minor ways, except for three decades following the mid-1870s, when the white pine timber along the Greenbrier and its tributaries was floated to Ronceverte in annual log drives. Following the timber harvest, the valley benefited from the conservation movement. Much of the upper part of the Greenbrier watershed was included in the Monongahela National Forest, and reforestation efforts, accelerated by the Depression-era Civilian Conservation Corps, restored timber to the mountainsides.

This restoration of the beauty of the valley has helped make recreation, which had its beginnings with pre-Civil War resorts at the mineral springs, a major part of the area's economy at the beginning of the 21st century.

Like other streams, the Greenbrier River at times needs its floodplain to carry all its water. The earliest settlements, located away from the river, did not have a problem with high water such as the major flood of 1877. However, following railroad construction and the building of communities in the floodplain, people and their property have been in danger from flooding. On November 5, 1985, the Greenbrier River crested at 23.95 feet, more than nine feet above flood stage. That flood killed 47 people and did extensive damage to several towns in West Virginia. On January 20, 1996, the Greenbrier River reached a record 24.33 feet, more than 10 feet above flood stage.

Flood control has been a topic of study and controversy since the 1930s. No action had been taken as of 2004, leaving the Greenbrier River the last major river in West Virginia to flow its entire length without man-made impediments.