Harrison County lies in north-central West Virginia, at the juncture of Interstate 79 and U.S. 50. The county covers 416.6 square miles, with a 2020 population of 65,921, a decline of nearly one-fourth from its peak of 85,296 in 1950. Clarksburg is the county seat. The rolling hills of Harrison County are drained by the West Fork River and its tributaries.

During the Indian wars of the early 1770s, forts were built along the rivers from the already established Fort Pitt to West's Fort at Jane Lew. Nutter's Fort, built in 1772 on Elk Creek, was one of the strongest. Two miles west of Nutter's Fort, where Elk Creek flows into the West Fork River and on land Daniel Davisson claimed through settlement in 1773, a community of settlers by 1780 had built their adjoining houses in a rectangle to give some protection. At a meeting of citizens, Samuel Shinn suggested their settlement be named Clarksburg in honor of Revolutionary War hero George Rogers Clark. So many people had settled on the West Fork by the end of the Revolution that the Virginia General Assembly in 1784 formed the new county, to be named for Benjamin Harrison, governor of Virginia, 1781-84.

The first U.S. judicial district west of the Alleghenies was established at Clarksburg in 1819. John George Jackson, member of Congress (1803-11; 1813-17), brother-in-law of Dolley Madison, and federal judge, may have been the influence that made Clarksburg for many years the ideal place for ambitious young lawyers to set up practice. From among these lawyers came Joseph Johnson, the only governor of Virginia (1852-56) from west of the mountains; John S. Carlile, who led the first movement for the formation of West Virginia, at the Clarksburg Convention, April 22, 1861; and John W. Davis, Democratic nominee for president in 1924. John George Jackson's cousin and law partner, Jonathan Jackson, was the father of Gen. Thomas Jonathan "Stonewall" Jackson, born in Clarksburg in 1824.

The Virginia legislature chartered Randolph Academy in Clarksburg in 1787, which it was hoped would be a worthy western counterpart to William and Mary College. George Towers arrived from England in April 1796 to teach at the school. A dedicated scholar, Towers set a high standard. The Northwestern Academy, described as a "fine classical school," was established in 1841, and the Clarksburg Independent School District in 1867. Harrison eventually had 10 public high schools, reduced through consolidation between 1970 and 1997 to five. Salem College, founded in 1888 and bought by Japanese interests in 1989, became Salem-Teikyo University and is now Salem International University. Fairmont State University has a Clarksburg branch. Clarksburg has had a business school since the 1880s. The local Catholic school system is capped by Notre Dame High School in Clarksburg.

Harrison County was cattle country by the mid-19th century. The rich local soil produces a lush bluegrass that made Harrison beef a favorite in the East. With the opening of the Northwestern Turnpike in 1838, great herds were collected at Clarksburg and moved by drovers to Baltimore. After 1857, the Baltimore & Ohio Railroad (B&O) improved transportation, and by 1863, Harrison County was first in West Virginia in the production of beef cattle. In 1923, Lost Creek was the largest cattle shipping point on the B&O system. The 19th-century mystery writer Melville Davisson Post made the Harrison County livestock country into a lush pastoral milieu for his upright rural detective, Uncle Abner.

As early as 1836, the Virginia Geological Report noted the county's rich coal deposits, and by 1903 Harrison County was fourth in the state in total tons of coal produced. Gushers sent petroleum into the sky at Salem and Shinnston at the turn of the 20th century. Funds from drilling on Hall's Run in the first decade of the century let Nathan Goff Jr. build in Clarksburg the Waldo Hotel, Goff Building, and the Oak Hall commercial building. Workers signed on in Italy to emigrate to Harrison County company towns to mine coal and, with native migrants from the interior counties, helped swell the population from 27,690 in 1900 to 74,783 in 1920.

The abundance of energy sparked myriad industries. Glass factories fueled by natural gas made window glass, marbles, containers, and tableware. A steel mill was built as was a zinc smelting plant. Spur railroad lines made Clarksburg the distribution center for the central portion of the state. Later, the intersection of Interstate 79 with U.S. 50 reestablished the Clarksburg-Bridgeport area as an economic and distribution center.

Hope Gas Company established its central offices in Clarksburg early in the 20th century. In mid-century its parent company, Consolidated Natural Gas Transmission Corporation, chose Clarksburg for its corporate headquarters. It is now known as Dominion Hope. The National Carbon Company opened a graphite plant in Anmoore in 1904. The plant is now Amsted Graphite Materials.

Veterans from a wide area of the state are served by the Veterans Administration Medical Center, built in 1950. Catholic and Protestant hospitals merged to occupy the United Hospital Center, erected in 1960 in Bridgeport. It is now part of the WVU Medicine system.

Seven golf clubs and numerous parks and athletic arenas provide recreation to Harrison Countians and their visitors.

In 2023, Harrison County's largest employers were WVU Medicine, the county school system, Walmart, Pratt & Whitney Engine Services, and MHI RJ Aviation. The region is served by North Central West Virginia Airport, opened originally in 1935 as Tri-County Airport, in Bridgeport, which has become the headquarters for several aeronautics companies.

Howard Mason Gore, a Harrison County native, was governor of West Virginia 1925-29. Nathan Goff Jr. was U.S. senator, 1913-19; Jennings Randolph, born and reared in Salem, was U.S. senator, 1958-85. The writer Melville Davisson Post (1869-1930) was born at Lost Creek. Legendary football coach John McKay (1923-2001) graduated from Shinnston High School in 1941. Novelist Meredith Sue Willis (b. 1946) is a native of Shinnston.