Wayne County was established January 18, 1842, from part of Cabell County. It was named for General "Mad Anthony" Wayne, a Revolutionary War hero who later defeated Ohio Indian tribes at the 1794 Battle of Fallen Timbers. Wayne County lies in the juncture of two of West Virginia's major rivers, the Big Sandy and the Ohio. The county occupies 512.3 square miles.

The town of Wayne is the county seat. Originally called Trout's Hill, the town was incorporated as Fairview in 1882 and the name changed to Wayne in 1911.

Although the southern half of the county was first to be settled, it remained sparsely populated and was slow to develop. The northern part, bordering Cabell County, expanded rapidly after the Civil War. Huntington was founded as the western terminus of the Chesapeake & Ohio Railroad in 1871 and in 1921 expanded its corporate limits westward into Wayne County.

Wayne County participated fully in the bustling post-Civil War history of the Big Sandy Valley. Steamboats plied the river on their way to headwaters towns as far east as Pikeville, Kentucky, while unpowered boats served points even farther upstream. Log drives carried the timber of three states down the Big Sandy to the Ohio River during the late 19th and early 20th centuries. The main line of the Norfolk & Western Railway was completed through Wayne County to its terminus at Kenova in 1890, and the railroad bridge across the Ohio was built two years later.

The area south of Wayne town experienced a growth spurt near the turn of the 20th century, after the Norfolk & Western Railway was completed and mining and timbering boomed in communities from East Lynn to Crum. There was a move to create a separate county that would have been called Clark or Wilson, with the county seat at Dunlow. The idea was opposed by residents in Wayne town and the northern towns of Ceredo and Kenova, and it eventually died. Another debate developed in the early 1920s when people in the north proposed to move the county seat to the Ceredo-Kenova area. A special election failed to get the required two-thirds majority.

Wayne County's population tripled from 7,852 in 1870 to 23,619 in 1900. Blessed with an abundant supply of coal, natural gas, and timber, the county population rose to a peak of 46,021 in 1980. In 2012, Wayne had an estimated population of 41,649.

In addition to its portion of Huntington and the town of Wayne, the county has three other incorporated communities, Fort Gay, Ceredo, and Kenova. Fort Gay, located where the Tug and Levisa forks meet to form the Big Sandy, was the first permanent settlement in Wayne County, about 1800. The town was chartered in 1875 as Cassville, and the name changed to Fort Gay in 1932.

Ceredo was founded in 1857 as an antislavery experiment by a group headed by Eli Thayer, a congressman from Massachusetts. Ceredo was the site of a Union stronghold, Fort Pierpont, during the Civil War. It was incorporated in 1866.

Kenova, located in the point between the Ohio and the Big Sandy rivers, is the westernmost town in West Virginia. It was founded in 1889 and chartered in 1894. The name is formed from the names of the three states that neighbor each other there, Kentucky, Ohio, and West Virginia. Kenova was a crossroads for competing railroads, the Baltimore & Ohio, the Chesapeake & Ohio, and the Norfolk & Western. At one time in the 1950s, it was said to have more trains passing through than any other place in America.

Wayne County has always been known for its strong family ties. A once-popular saying was that the county is "owned by the Frys, run by the Fergusons, and populated by the Adkinses." The Fry family, which was headed by state legislator Lucian Fry, acquired several thousand acres of coal and timber in southern Wayne County. The Ferguson family has long been prominent at the county courthouse. Charles W. Ferguson II (1892—1976) was circuit judge from 1928 to 1967, and his son, C. W. Ferguson III (1920—95), succeeded him, serving until 1984. Milton J. Ferguson, the brother of the elder judge and a U.S. attorney, was responsible for prosecuting Governor Barron and members of his administration. A Democrat who had served in Governor Marland's administration, Ferguson ran unsuccessfully for governor in his party's primary in 1956.

Other prominent Wayne County names include Maynard, Perry, Ross, Napier, and Vinson. Sam Vinson (1833—1904) owned most of the land that became Westmoreland, the Wayne County section of Huntington. His son-in-law, Jim Hughes, was a congressman. His son, Zachary Taylor Vinson, was a well-known lawyer, and his daughter, Mary Vinson Clark, was instrumental in building Vinson High School.

Wayne County is the birthplace of the contemporary Christian singer and composer Michael W. Smith, football player Buzz Nutter, and major league pitcher Donnie Robinson. Fanny Belle Fleming, better known as Blaze Starr, a nightclub stripper in Baltimore and one-time paramour of Louisiana Gov. Earl Long, is a native Wayne Countian.

The largest companies operating in the county include Ashland Chemical Co., Sunoco Chemical, Hamer Lumber, Rockspring Development, Pen Coal Company, and Kanawha River Terminal. Wayne County has a variety of recreational areas, including Beech Fork State Park and Beech Fork Lake, East Lynn Lake, and Cabwaylingo State Forest. It also is home of Camden Park near Huntington, which is West Virginia's only surviving amusement park.