Built between 1811 and 1837, the 620-mile (1,000 km) road connected the Potomac and Ohio Rivers and was a main transport path to the West for thousands of settlers.

When improved in the 1830s, it became the second U.S. road surfaced with the macadam process pioneered by Scotsman John Loudon McAdam.

It received its name during the colonial-era French and Indian War of 1753–1763 (also known as the Seven Years' War in Europe), when it was constructed by British General Edward Braddock, who was accompanied by Colonel George Washington of the Virginia militia regiment in the ill-fated July 1755 Braddock expedition, an attempt to assault the French-held Fort Duquesne.

In June 2012, a monument and plaza were built in that town's Riverside Park, next to the historic original starting point.

Completed in 1824, these feeder routes formed what is referred to as an eastern extension of the federal National Road.

By that time, railroads were beginning to compete long-distance transportation, and the Baltimore and Ohio Railroad was being built west from Baltimore to Cumberland, mostly along the Potomac River, and then by a more direct route than the National Road across the Allegheny Plateau of West Virginia (then Virginia) to Wheeling.

The mostly parallel Interstate 70 (I-70) now provides a faster route for through travel without the many sharp curves, steep grades, and narrow bridges of US 40 and other segments of the National Road.

Heading west from Hancock in western Maryland, I-70 takes a more northerly path to connect with and follow the Pennsylvania Turnpike (also designated as I-76) across the mountains between Breezewood and New Stanton, where I-70 turns west to rejoin the National Road's route (and US 40) near Washington, Pennsylvania.

Three of the road's original toll houses are preserved: Additionally, several Old National Pike Milestones—some well-maintained, others deteriorating, and yet others represented by modern replacements—remain intact along the route.

There, travelers could turn off to Pittsburgh or continue west through Uniontown and reach navigable water, the Monongahela River, at Brownsville, Pennsylvania, which was by then a major outfitting center and riverboat-building emporium.

The western terminus of the National Road at its greatest extent was at the Kaskaskia River in Vandalia, Illinois, near the intersection of modern US 51 and US 40.

The National Road continued into Indiana along modern US 40, passing through the cities of Terre Haute and Indianapolis.

Within Indianapolis, the National Road used the original alignment of US 40 along West and East Washington Street (modern US 40 is now routed along I-465).

The road cut across southwestern Pennsylvania, heading southeast for about 90 miles (140 km) before entering Maryland.

The approval process was a hotly debated subject because of the removal of the original macadam construction that made this road famous.