Mullens, at the junction of Slab Fork Creek and the Guyandotte River in Wyoming County, was incorporated on September 17, 1912. It was named for A. J. Mullins, who owned the land upon which the town was built. At some point, the spelling of the town's name changed to Mullens with an "e" rather than an "i."

In 1902 and 1904, Mullins sold land to the Deepwater Railway Company for a right-of-way through his farm. Deepwater merged with the Tidewater Railway Company in Virginia to form the Virginian Railway, and completion of the Virginian in 1909 sparked an industrial boom. The W.M. Ritter Lumber Company bought large tracts of timber in the area and established a mill at Maben, five miles from Mullens. The Virginian built a rail yard near Mullens, which helped establish the town as the commercial heart of the new Winding Gulf coalfield.

Between 1917 and 1919, the young town experienced two fires and a flood, destroying many of the original wood-frame buildings. Afterward, a city ordinance required that buildings be constructed of brick or stone. The five-story Wyoming Hotel, designed by Alex Mahood, opened in 1918. The Mullens Historic District is listed in the National Register of Historic Places.

Mullens was Wyoming County's largest incorporated town with a peak population of 3,544 in 1960, but the number of residents fell as coal employment shrank due in large part to mine mechanization. A flood in July 2001 inundated downtown businesses with seven feet of water, and the town has struggled to recover since then. The 2020 population was 1,475, its lowest total in 100 years. As of that year, Mullens had 13 more people than the county’s second-largest town, Oceana.

Mullens is home to the Caboose Museum, housing local memorabilia, and the town hosts the Dogwood Festival each May. Mike D'Antoni, a longtime coach in the National Basketball Association, grew up in Mullens. Other Mullens natives include D’Antoni’s brother Dan, head coach of Marshall University’s men’s basketball team, and former professional boxer Christy Martin. Rick Tolley, who grew up in Mullens, was Marshall University football head coach at the time of the 1970 plane crash that killed 75 people, including Tolley.

Read the National Register nomination for the town’s historic district.