The North Branch of the Potomac River is one of two branches of the Potomac and usually thought of as the river's main stem. The historic spring at the Fairfax Stone is considered the head of the North Branch and of the Potomac itself, marking in colonial times the western extent of Lord Fairfax's lands. From the Fairfax Stone the North Branch flows to Green Spring, Hampshire County, where it joins the South Branch to become the Potomac proper. Throughout its length, the North Branch forms the boundary between West Virginia and Maryland.

The tributaries of the North Branch include the Stony River and Patterson Creek, in West Virginia, and Wills and Georges creeks and the Savage River, in Maryland. Cumberland, Maryland, is the largest city on the North Branch. Other communities include Keyser, the county seat of Mineral County, and Ridgeley, Wiley Ford, Piedmont, Gormania, and Bayard, West Virginia, and several towns on the Maryland side. The North Branch is dammed upstream from Piedmont, forming the Jennings Randolph Lake.

The Potomac headwaters form the western boundary of the Atlantic slope, interlacing in the high Alleghenies with the headwaters of the Ohio to define the eastern continental divide. This is historic country, representing for many years the limits of colonial American settlement. The frontier wars were fought in the North Branch Valley and neighboring regions for much of the 18th century, with young George Washington in charge of Virginia's defense during the critical French and Indian War period. Washington had forts built at Fort Ashby, on Patterson Creek in Mineral County, and elsewhere in the North Branch watershed.

The Potomac Valley forms a natural transportation corridor, used heavily from early times to the 20th century. The Chesapeake & Ohio Canal, now a national park paralleling the river, was built as far west as Cumberland in 1850. The coming of the Baltimore & Ohio (B&O) Railroad in the 1830s and 1840s further transformed the region. The B&O largely follows the Potomac and the North Branch from Harpers Ferry to Piedmont, and its completion opened rich coal and timber lands to development. West Virginian Henry Gassaway Davis, U.S. senator and major industrialist and once a resident of Piedmont, was among those to exploit the region.

Unlike the pastoral South Branch Valley, the North Branch for much of its history has made its living largely by industry and by natural resource extraction. Coal has been mined in the North Branch region from the 19th century to the present, and there are industrial sites at Piedmont and at many other points in the watershed. Pollution has been an issue, and steps were taken in the last half of the 20th century to rectify the problem. Millions of people in metropolitan Washington and other downstream areas depend on the water of the Potomac watershed.

All of Mineral County is drained by the North Branch and its tributaries, as are most of Grant and parts of Tucker and Hampshire counties. Much of western Maryland lies within the watershed, as well. The North Branch flows 75.8 miles from its head to its mouth, and is the major geographic feature tying together a diverse bi-state region.