Except for a small portion of its headwaters in West Virginia, the North Branch Potomac River is considered part of Maryland to the low-water mark on the opposite bank.

The source of the North Branch is at the Fairfax Stone located at the junction of Grant, Tucker, and Preston counties in West Virginia.

The source of the North Branch Potomac River is at the Fairfax Stone located at the junction of Grant, Tucker and Preston counties in West Virginia.

From the Fairfax Stone, the North Branch Potomac River flows 27 mi (43 km) to the man-made Jennings Randolph Lake, an impoundment designed for flood control and emergency water supply.

The South Branch's source is northwest of Hightown along U.S. Route 250 on the eastern side of Lantz Mountain (3,934 ft) in Highland County.

At Forks of Waters, the South Branch joins with Strait Creek and flows north across the Virginia/West Virginia border into Pendleton County.

Into Grant, the South Branch follows the western side of Cave Mountain through the 20-mile (32 km) long Smoke Hole Canyon, until its confluence with the North Fork at Cabins, where it flows east to Petersburg.

The South Branch is traversed by the Northwestern Turnpike (U.S. Route 50) and joined by Sulphur Spring Run where it forms Valley View Island to the west of town.

Flowing north of Romney, the river still follows the eastern side of Mill Creek Mountain until it creates a horseshoe bend at Wappocomo's Hanging Rocks around the George W. Washington plantation, Ridgedale.

This stretch encompasses the section of the Potomac River from the confluence of its North and South Branches through Opequon Creek near Shepherdstown, West Virginia.

[16] In 1608, Captain John Smith explored the river now known as the Potomac and made drawings of his observations which were later compiled into a map and published in London in 1612.

The spelling of the name has taken many forms over the years from "Patawomeck" (as on Captain John Smith's map) to "Patomake", "Patowmack", and numerous other variations in the 18th century and now "Potomac".

[35] In 1940 Congress passed a law authorizing the creation of an interstate compact to coordinate water quality management among states in the Potomac basin.

[36] Beginning in the 19th century, with increasing mining and agriculture upstream and urban sewage and runoff downstream, the water quality of the Potomac River deteriorated.

One of the significant pollution control projects at the time was the expansion of the Blue Plains Advanced Wastewater Treatment Plant, which serves Washington and several surrounding communities.

[37] Enactment of the 1972 Clean Water Act led to construction or expansion of additional sewage treatment plants in the Potomac watershed.

[36] By the end of the 20th century, notable success had been achieved, as massive algal blooms vanished and recreational fishing and boating rebounded.

Still, the aquatic habitat of the Potomac River and its tributaries remain vulnerable to eutrophication, heavy metals, pesticides and other toxic chemicals, over-fishing, alien species, and pathogens associated with fecal coliform bacteria and shellfish diseases.

[38] On November 13, 2007, the Potomac Conservancy, an environmental group, issued the river a grade of "D-plus", citing high levels of pollution and the reports of "intersex" fish.

[40] In March 2019, the Potomac Riverkeeper Network launched a laboratory boat dubbed the "Sea Dog", which will be monitoring water quality in the Potomac and providing reports to the public on a weekly basis;[41] in that same month, the catching near Fletcher's Boat House of a Striped Bass estimated to weigh 35 lb (16 kg) was seen as a further indicator of the continuing improvement in the health of the river.

[2] The highest average daily flow ever recorded on the Potomac at Little Falls, Maryland (near Washington, D.C.), was in March 1936 when it reached 426,000 cubic feet (12,100 m3) /s.

[2] The lowest average daily flow ever recorded at the same location was 601.0 cubic feet (17.02 m3) /s in September 1966[2] The highest crest of the Potomac ever registered at Little Falls was 28.10 ft, on March 19, 1936;[43][28] however, the most damaging flood to affect Washington, DC and its metropolitan area was that of October 1942.

In its first state constitution adopted in 1776, Virginia ceded its claim to the entire river but reserved free use of it, an act disputed by Maryland.

A Special Master appointed by the Supreme Court to investigate recommended the case be settled in favor of Virginia, citing the language in the 1785 Compact and the 1877 Award.

In addition to stocking the river with more than 22 million shad fry, the Project supervised the construction of a fishway that was built to facilitate the passage of adults around the Little Falls Dam on the way to their traditional spawning grounds upstream.

There is no record of early settlers having observed marine mammals in the Potomac, but several sightings of Atlantic bottle-nosed dolphins (Tursiops truncatus) were reported during the 19th century.