New Martinsville is located on the Ohio River at the junction of State Routes 2 and 20. Edward Dulin is believed to have been the first settler of European descent in 1773. Dulin was killed by Indians, and his daughter sold some of his land to Presley Martin. In 1838, "Martinsville" was incorporated and in 1846 became the county seat of newly formed Wetzel County. Long called "New" Martinsville to distinguish it from the other Martinsville, Virginia, the town was officially renamed in 1871.

New Martinsville has seen massive floods, which made the streets navigable only by boat. One of the worst floods hit on March 19, 1936, and the city was again flooded in September 2004.

New Martinsville is the meeting place of the former West Virginia Short Line, now part of CSX, and the Ohio River Division of the Baltimore & Ohio Railroad, now also CSX. In the early part of the 20th century, the town bustled with a tannery, planing mill, foundry, brick works, oil well supply, and the Viking Glass Company. Now, many residents commute to surrounding plants and mines. Others work at Wetzel County Hospital or New Martinsville's branch of West Virginia Northern Community College.

New Martinsville is a partner in the Hannibal locks and dam hydroelectric facility. Located on the Ohio River at the north end of town, the hydro plant contributes substantially to the city budget. New Martinsville operates one of only two municipal electric systems in West Virginia and residents benefit from low electric rates.

In 1925, Gloria Swanson's film Stage Struck was filmed in and around New Martinsville. Hydroplane racers from around the world participate in the River Heritage Days Regatta each year. The population of New Martinsville in 2020 was 5,186, a 27.1 percent decrease from its peak of 7,109 in 1980.