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 on the National Register of Historic Places.

Mullens became Wyoming County's largest incorporated town with a peak population of 3,449 in 1950, but the number of residents fell as coal employment shrank. A flood in July 2001 inundated the downtown businesses with seven feet of water, and the town has struggled to recover since then. The population in 2010 was 1,559. Mullens is home to the Caboose Museum, housing local memorabilia, and the town hosts the Dogwood Festival each May. Mike D'Antoni, coach of the Los Angeles Lakers, grew up in Mullens.

Read the National Register nomination for the Mullens Historic District.