Moundsville, the county seat of Marshall County, is located on the Ohio River at the mouth of Grave Creek. Joseph, Samuel, and James Tomlinson built the first cabin on the flats of Grave Creek in 1771. In 1798, Joseph Tomlinson laid out lots in a tract named Elizabethtown, in honor of his wife, Elizabeth Harkness Tomlinson. In 1832, neighboring Moundsville was established on land owned by Simeon Purdy. Elizabethtown, incorporated in 1830, was named county seat when Marshall County was formed in 1835. The first courthouse was used from 1836 until 1875; the second, and current, courthouse opened in 1876.

Moundsville was named for Grave Creek Mound, built by Adena Indians between 250 B.C. and 150 B.C. The largest earthen, conical burial mound in North America, Grave Creek Mound is 240 feet in diameter and 62 feet high. It is maintained by the state of West Virginia as part of the Grave Creek Mound Archaeological Complex, which includes the adjacent Delf Norona Museum, named for Delf Norona, a founder of the West Virginia Archeological Society who helped establish a museum on the site in 1952.

In 1866, Elizabethtown and Moundsville were consolidated under the name of Moundsville. The first recorded school was established in the community in 1799; school sessions were held regularly by 1826. Free schools were established in Moundsville in 1866. The first public building was a jail completed in 1836. In July 1866, work began on the West Virginia Penitentiary; the maximum-security prison remained in operation in Moundsville until 1995. After the prison was closed, the Northern Regional Jail and Correctional Facility was constructed in Moundsville.

Early industries included iron works, factories, tanneries, mills, and coal mining. In the 20th century, Fostoria Glass Company produced art glass dinnerware and U.S. Stamping made enamelware at Moundsville. Novelist Davis Grubb (1919-80) was born in Moundsville and often featured the community in his writing, usually as the fictitious Glory, West Virginia. Two of his novels were adapted as major motion pictures, Night of the Hunter (1955) and Fools' Parade (1971), both filmed in Moundsville.

In 2020, Moundsville had a population of 8,122, a 46.4 percent decrease from its peak of 15,163 in 1960 due largely to the closing of factories.