A lack of dependable all-weather transportation routes over the Appalachian Mountains was among the factors that kept colonists within 150 miles of the coastline throughout the colonial period in America. Despite a lack of reliable interior roads, settlers began to stream over the mountains in increasing numbers after the Revolution. With no state or private enterprise possessing the resources to develop the infrastructure to bind the nation, in 1802 the federal government proposed an all-weather road to connect eastern markets with the westward-flowing waters of the Ohio River. Congress authorized construction of the National Road from Cumberland, Maryland, to Wheeling in 1806.

President Jefferson appointed three commissioners who employed a six-member surveying team to locate a route for America's first interstate highway. Civilian contractors bid on the right to build it for the U.S. Treasury Department under the direction of its secretary, Albert Gallatin, and construction superintendent David Shriver. Road crews consisting primarily of Irish and English immigrants started in Maryland in 1811 and continued working westward through Pennsylvania and West Virginia in subsequent years. Mail service on the unfinished road began to Wheeling in 1818; workers completed construction on the original 131-mile route in 1821 at a cost of $1.7 million.

Officially designated as the Cumberland Road, the highway crossed the rugged mountains of western Maryland before leveling out and taking a general northwesterly course through the Pennsylvania countryside to Ohio County, (West) Virginia. Following the valley of Wheeling Creek, it passed Roney's Point, Triadelphia, and Elm Grove to its western terminus on the Ohio River. Wheeling's strategic position at the confluence of river and road led to its rapid growth as a major inland port for goods and passengers moving between the east and west. A river ferry connected Wheeling with Zane's Trace, an important post road across southern Ohio to Limestone (now Maysville), Kentucky. Part of the trace later became incorporated into the western extension of the National Road laid out and built in the 1820s—30s through Ohio and Indiana to Vandalia, Illinois.

Heavy freight wagons and livestock clogged the highway and rapidly destroyed the roadbed east of Wheeling. Project management passed to the U.S. Army Corps of Engineers in 1825 as federal interest in the highway lagged in light of decreasing appropriations and increasing competition from railroads and canals. As a result, the federal government agreed to overhaul the roadbed, construct a series of tollhouses, and give the road to the states for operation as a turnpike. In total, the government spent $6.8 million to build and repair the road from Cumberland to Vandalia. After the Baltimore & Ohio Railroad reached Wheeling in the 1850s, the National Road entered a period of decline that lasted until the automobile era when it was incorporated into U.S. 40, a major transcontinental route from Atlantic City to San Francisco.

Constructed in 1817, the stone arch bridge at Elm Grove carries the National Road over Little Wheeling Creek and is the oldest bridge in the state. The other historic bridge associated with the National Road in West Virginia is the Wheeling Suspension Bridge, which opened in 1849, and carries traffic over the Ohio River.

Although modern Interstate 68 has superseded it, the National Road survives as a scenic byway that offers a slower-paced alternative for travelers who wish to experience the 200-year history of America's first federal highway. In 2002, the 16-mile stretch of National Road that passes through West Virginia was designated as the state’s first All-American Road.