Doddridge County was formed February 4, 1845, from parts of Harrison, Lewis, Ritchie, and Tyler counties. It was named for Philip Doddridge, a Western Virginia congressman, state legislator, and member of the Virginia Constitutional Convention of 1829-30.

Located in the hills of north-central West Virginia, the area was first settled by European Americans about 1800. Indian trails, including the Monongahela-Scioto and the Middle Island trails, village sites, and burial mounds are evidence of an earlier prehistoric Native presence. The land that eventually became the county seat of West Union was part of 20,000 acres patented by James Caldwell in 1787 and settled by brothers Nathan, William, and Joseph Davis in 1808. The county encompasses 320.6 square miles.

The Northwest Turnpike, completed in 1838, connected Winchester and Parkersburg and resulted in the growth of many Western Virginia communities, including West Union. Likewise, the Northwestern Virginia Railroad, a subsidiary of the Baltimore & Ohio that ran from Grafton to Parkersburg, brought increased economic opportunity to Doddridge and surrounding counties when it was completed in the 1850s. Lumber became a leading enterprise in Doddridge County, supplying the burgeoning rail industry with crossties.

The Civil War interrupted the development of the county. Doddridge's sentiments were with the North. It sent representatives to the first and second Wheeling conventions, which reestablished a loyal government of Virginia and provided for the creation of West Virginia. Four Union units were raised in the county: Company H, 4th West Virginia Cavalry; Company C and Company M, 6th West Virginia Volunteer Infantry; and Company A, 14th West Virginia Volunteer Infantry. Before the war, a tavern and stagecoach stop about one mile from West Union was reputed to have been part of the Underground Railroad. Proprietor Luke Jaco opened the establishment about 1845 and may have used a nearby cave to harbor runaway slaves on their way to the Ohio River.

As the end of the 19th century approached, timber was supplanted in the local economy by oil and gas. The Center Point oil pool was opened by the South Penn Oil Company in 1892; between 1900 and 1929, many Doddridge wells commonly produced 50 to 100 barrels of petroleum per day. In addition to South Penn, major companies included Carter Oil, the Philadelphia Company, Carnegie Gas, and Hope Natural Gas. Numerous local independent drillers also worked the oil and gas fields.

Oil and gas spawned other industries in the county. These included carbon manufacturing, which used natural gas as a raw material, and glass making, which used gas as a cheap fuel. In the early 1900s, Ideal Glass and Doddridge County Window Glass operated in West Union; Acme Carbon, Castle Brook Carbon, Mountain State, and Southern Carbon companies were located in and around Smithburg.

Oil and gas production dropped off during the Great Depression, but new drilling began during World War II. Doddridge experienced a second drilling boom in the 1960s. A well at the mouth of Doe Run was found to contain 10 million cubic feet of gas and flowed 200 barrels of oil a day. Today, oil and gas production remains the county's most important industry.

Although the terrain is quite hilly, farming is important in Doddridge. Livestock, particularly cattle and sheep, and poultry are the county's leading agricultural products. Doddridge is part of the "Bluegrass Belt" that stretches from Tennessee north into West Virginia and southern Pennsylvania, providing rich pastures. The county's red, white, and yellow clay soil (with some limestone deposits) is also suitable for growing grain. Doddridge is well-drained by a number of streams and creeks, the most important being Middle Island Creek, which flows northwestward for more than 75 miles to the Ohio River.

The significance of both industry and agriculture in West Virginia is depicted in the state seal, which was designed by Joseph Diss Debar, a French immigrant who settled in West Virginia in 1846. In the early 1850s, Diss Debar founded the Doddridge County community of St. Clara, named for his first wife, Clara Levassor. As a Doddridge County delegate to the legislature, he helped create a state office of immigration and was named the first West Virginia commissioner of immigration in 1864.

Doddridge County is the birthplace of the only West Virginian ever to be elected a member of the U.S. House of Representatives, the U.S. Senate, and the state's governor. Matthew Mansfield Neely was born near Grove, November 9, 1874. Neely began his political career as mayor of Fairmont. Until his death from cancer in 1958, Neely was a dynamic and controversial figure in state and national Democratic politics.

Doddridge County is divided into four magisterial districts: Beech, Maple, Oak, and Pine. The county is served by one early learning academy, one elementary school, and one middle school. Doddridge County High School, now the county's only secondary school, was created in 1933 when the newly instituted county school system consolidated Carr High School and West Union High School.

As in much of West Virginia in the early 20th century, poor roads made travel through Doddridge difficult. The county's first roads were paved in 1914, and during the Depression many secondary roads were paved by the federal Works Progress Administration. In 1964, work began at Parkersburg to make U.S. 50 a four-lane highway, and the Doddridge section of the highway was completed between 1964 and 1972. Today, U.S. 50, which is Corridor D in the Appalachian Development Highway System, is the main transportation artery through the county.

Population dropped sharply between 1940 and 1960, from 10,923 to 6,970, as West Virginia suffered a period of sustained out-migration, a reflection of shifting national economics. Doddridge made solid gains between 1970 and 1980, from 6,389 to 7,433, when West Virginia became a destination of the back-to-the-land movement; lost population in the 1980s; and has since rebounded. The 2020 population of Doddridge County was 7,808.

In 2023, Doddridge County's largest employers were the county school system, Triple H Enterprises, Antero Resources, Marathon Petroleum Logistics, and the county commission.