Weston was founded in 1817 as the county seat of Lewis County. It was initially called Preston, then Fleshersville. In 1819, Weston became the permanent name. The building of the Staunton-Parkersburg and the Weston & Gauley Bridge turnpikes spurred development, and Irish and German immigration hastened population growth. In 1858, Weston was chosen as the site for Virginia's third mental health hospital; construction was under way when the Civil War began and completed in 1880. The area, alternately occupied by Union and Confederate troops, saw only skirmishes during the war.

The state hospital's economic impact cannot be overstated. Asylum-generated commerce made feasible a narrow gauge railroad connecting Weston with Clarksburg in 1879. Prosperity brought brick public schools for whites and blacks. Grand homes went up. Weston had telephones in 1885; electric lights in 1890; and a municipal water plant, sanitary and storm sewer systems, and brick-paved streets before 1900. Population quadrupled between 1865 and 1900.

Local natural gas discoveries at the turn of the century made Weston a glass-manufacturing center. Division offices for the Baltimore & Ohio Railroad followed. Population doubled again before 1930. With a well-diversified economy, Weston suffered less than most towns during the Depression. After World War II, the strip mining of coal increased local commerce. The glass industry enjoyed its best years during the middle of the 20th century, until foreign competition encroached. The city’s population, which peaked at 8,945 in 1950, had declined to 3,943 by 2020, making it West Virginia’s 32nd largest city.

Closed plants and the end of mining cost Weston its rail service, but Interstate 79 and Corridor H brought new development to the outskirts of town. The building of Stonewall Jackson Dam and Lake on the West Fork eliminated flooding. New elementary, middle, and high schools were built in the 1980s and '90s. A new hospital opened in 1972. Weston State Hospital closed, but a new mental health facility—the William R. Sharpe Jr. Hospital—was built in 1994. Weston also is home to Stonewall Jackson Memorial Hospital, part of the Mon Health network.

The former Weston State Hospital, a National Historic Landmark, is now operated as a tourist attraction under its original name, the Trans-Allegheny Lunatic Asylum. It contains a museum and offers history and paranormal tours.