Upshur County was created on March 26, 1851, from parts of Randolph, Lewis, and Barbour counties, with Buckhannon as the county seat. Located in the north-central part of West Virginia, Upshur County is crossed by four-lane Corridor H (U.S. 33) and is within a few miles of Interstate 79. Coal mining, oil and gas, timbering, farming, and small industry are the major industries. Historically, Upshur had six magisterial districts, which have now been reduced to three. With 354.7 square miles, the county is served by one high school, one middle school, seven elementary schools, and a technical center. In 2020, its population was 23,816, a slight decline from its peak total of 24,254 in 2010. The county rises from rolling foothills to mountains of more than 3,000 feet in the rugged southeastern section. The Buckhannon River is the major waterway, flowing north nearly the entire length of the county.

Evidence indicates early Indian habitation. Indian Camp Rock, Ash Camp, and remnants of village sites on Hackers Creek support this conclusion. In the 1760s, John and Samuel Pringle, deserters from the British army at Fort Pitt, made their way into the area and for about three years lived in a hollow sycamore tree on the banks of the Buckhannon River. By 1770, a permanent settlement was made in the Buckhannon Valley by families named Pringle, Hacker, Cutright, Hughes, White, Jackson, Westfall, Brake, Bozarth, Strader, Post, Bush, Lorentz, Carper, Rohrbough, and others. Bush's Fort was the main defense until it was destroyed by Indians in 1782. The last Indian foray in Upshur County was the massacre of the Bozarth family in 1795.

Beginning in 1801 with Zedekiah Morgan, large numbers of New Englanders settled in Upshur County, mostly in the French Creek area. Family names from this migration included Gould, Young, Phillips, Burr, Tenney, Brooks, Bunten, Thayer, Leonard, and others. However, little of the 100,000 acres acquired by the Ruggles Woodbridge Land Company through speculation, and sold to these families, had a clear title. By 1830, more than half of these New Englanders had moved farther west, but the effect of this Yankee population can still be felt today with its influence on education, politics, and religion in Upshur County and beyond. The Brooks family especially has left a major mark on such institutions as West Virginia University, and Oglebay Park, as well as the natural sciences.

In 1810, the Methodists organized their first church here, referred to as the Carper Church. Today, the United Methodists are still the dominant denomination in the county. West Virginia Wesleyan College was established in Buckhannon as the West Virginia Conference Seminary in 1887 and opened its doors in 1890. Other educational institutions included the Buckhannon Male and Female Academy, 1847-66; French Creek Academy, 1871-85; West Virginia Classical and Normal Academy, 1882-97; and the Indian Camp Normal School, 1913-18, whose building still stands today.

Throughout the Civil War, Upshur County was firmly Unionist. The only real battle in the county took place August 30, 1862, near Water Tank Hill, during the Jenkins Raid of Confederate Cavalry. Nearly three dozen Union soldiers were killed, wounded, or taken captive. That night, bonfires lighted Main Street as Confederate soldiers looted and pillaged Buckhannon. The greatest calamity to befall the county during the war was the capture of the Upshur Militia on September 12, 1863, at Centerville (now Rock Cave). Of the 70 captives, 43 died in Southern prisons, including some at dreaded Andersonville, Georgia. They left behind 27 widows and 83 children.

The West Virginia Central & Pittsburg [sic] Railway first entered Upshur County in 1883, and Henry Gassaway Davis built his Coal & Coke Railway across the county in 1904. The railroads brought industry to the area. Timbering was heavy in the southern end of the county at the turn of the 20th century. In 1901, the first coal was commercially mined, at Lorentz by the Pleasant Valley Coal Company. An explosion there in 1907 cost the lives of 12 men, the largest mining disaster in Upshur County history. Adrian developed as a major mining center with other communities following close behind. In recent times, large deep mine and strip mine operations have contributed to Upshur's economy and to its environmental problems. The county also has had a tannery, chemical company, glass plants, a printing company, as well as the Corhart Refractories, Uponor ETI, Trus Joist MacMillan, Coastal Lumber, and many smaller operations. St. Joseph's Hospital was founded in 1921 by the Pallottine Missionary Sisters.

In 2023, Upshur County's largest employers were the county school system, WVU Medicine, Weyerhaeuser Natural Resources, West Virginia Wesleyan College, and Walmart.

In 1936, the Central West Virginia Strawberry Festival was organized to encourage agricultural production. The festival continues at Buckhannon, with less emphasis on farming. The West Virginia Farm Bureau state headquarters is located in Buckhannon, as well as the West Virginia Division of Highways state headquarters for equipment repair and distribution, located in a landmark cut-stone building on the outskirts of town. The United Methodist Annual Conference is held on the campus of Wesleyan College. The West Virginia State Wildlife Center is located at French Creek, where it was established in 1923.

Upshur County has produced many prominent individuals. Daniel D. T. Farnsworth, second governor of West Virginia, was a member of the Buckhannon family which originally owned all of the property where the city now stands. Arthur B. Waugh, native of southern Upshur County, was a Pulitzer Prize winner in journalism in 1935. Pare Lorentz was a leading documentary filmmaker of Franklin Roosevelt's New Deal. Naturalist Maurice Brooks authored the noted The Appalachians and much more. Jean Lee Latham received the Newbery Award for her Carry On, Mr. Bowditch in 1956. Author Stephen Coonts grew up in Buckhannon, and Jayne Anne Phillips is an Upshur native. Annie Latham Bartlett was well-known for her sculptural works and exhibited at the New York World's Fair in 1939. Her father, Gen. George R. Latham, served as consul to Australia in the 1860s. Warren Jackson and Laura Jackson Arnold, brother and sister to the famous Thomas T. J. "Stonewall" Jackson, both lived, died, and are buried in Upshur County. It was also home to one of West Virginia’s finest wood sculptors, Wolfgang Flor.