Williamstown is located on the Ohio River north of Parkersburg, at the junction of Interstate 77 and State Route 2. It is the site of one of the earliest settlements in Wood County, having been claimed in 1770 by brothers Joseph and Samuel Tomlinson. The property later passed to their sister, Rebecca Tomlinson Martin Williams. She and her husband, Isaac Williams, permanently settled the 400-acre Tomlinson tract in 1787, and Williamstown was named for them.

Williamstown is situated opposite the mouth of the Muskingum River, the present site of Marietta, Ohio, and an important and strategic point in the early history and prehistory of the Ohio Valley. Buckley Island is located in the Ohio River at Williamstown.

Once called Duncan and also Williamsport, the community was chartered as Williamstown in 1822. It was incorporated in 1921. Williamstown has long been a major Ohio River crossing point. One of Western Virginia's important early roads terminated there, and in 1800 Isaac Williams was authorized to operate a ferry to carry traffic to the Ohio shore. Early ferry flats and canoes were succeeded by a steam ferry, and a bridge was built in 1905. Today, the Interstate 77 Ohio River bridge is located nearby.

Williamstown's Tomlinson mansion, the 1839 home of Joseph Tomlinson III, was added to the National Register of Historic Places in 1974. John James Audubon was once a guest there. The Henderson Hall Historic District, which neighbors Williamstown to the south, was added to the National Register in 1986. It encompasses sites associated with the Tomlinson-Henderson family and includes three Indian burial mounds within its bounds. The Fenton Art Glass Company made hand-made glass at Williamstown from 1906 until 2011.

Its population in 2020 was 2,997, just slightly below its peak of 3,095 in 1980. As of 2020, it was West Virginia’s 41st largest city.