Sistersville is located in Tyler County, on the Ohio River midway between Parkersburg and Moundsville. It is situated on State Route 2, the main north-south highway in this part of West Virginia, at the intersection with State Route 18. Sistersville is located on the famous "Long Reach" of the Ohio, an unusual 20-mile straight stretch in the river. A toll ferry, the last in the state, conveys automobiles and passengers across the Ohio at Sistersville.

Charles Wells settled in the area about 1800, and within a few years his tavern and farm were known to travelers. Wells left his land to daughters Sarah and Delilah. They laid out town lots about 1815, and Sistersville was named for these enterprising sisters. The town was incorporated in 1839. Like some other Ohio Valley communities, Sistersville had mixed allegiances during the Civil War, with a sizable minority favoring the Confederacy.

The Ohio River Railway was built through Sistersville in 1884, and the town underwent an industrial boom with the local discovery of oil a few years later. Fortunes were made as derricks appeared even in the residential areas. Population in the Sistersville's area was estimated to have increased by more than tenfold during the boom, from about 600 in 1888 to 7,000 in 1898. The Wells Inn, a downtown landmark now listed in the National Register of Historic Places, opened as the Wells Hotel in 1895, at the height of this prosperity.

After the oil boom subsided in the early 20th century, Sistersville settled down as a quiet residential town. It remains so today, with a population of 1,413 in 2020.

Read the National Register nomination for the Wells Hotel.