Kenova lies at the westernmost point of West Virginia, in Wayne County at the juncture of U.S. 60 and U.S. 52 and the confluence of the Ohio and Big Sandy rivers. L. T. Peck, the founder, chose the site just west of Ceredo because it was the place where the Norfolk & Western Railroad proposed to build the first bridge across the Ohio River above Cincinnati. Peck organized the Kenova Association, purchased 900 acres of bottomland, and started his town in 1889. The site was named Kenova from the abbreviations of the three adjoining states: "Ken" for Kentucky, "O" for Ohio, and "Va" for (West) Virginia.

In 1890, the original line of the Norfolk & Western running from Kenova down to Mingo County was completed. There was an influx of engineers, firemen, conductors, brakemen, and other railroad personnel. In 1892, the N&W Ohio River bridge was completed. That year the Baltimore & Ohio Railroad also entered the community. Kenova was incorporated as a town in 1894. From its founding into the early 1900s, Kenova was predominantly a railroad town and served as a terminal for the N&W, C&O, and B&O lines.

During the 1920s, Kenova received its charter as a city. Kenova experienced two disastrous floods, in 1913 and 1937, but residents recovered from these calamities and the town grew. Although Kenova's population has declined from a peak of nearly 5,000 in 1970 to 3,216 in 2010, it remains the largest city in Wayne County.