Hampshire, West Virginia's oldest county, is located in the Eastern Panhandle west of the Blue Ridge and Shenandoah River and east of the Allegheny Mountains, in the geological region known as the Ridge and Valley Province. Bordered to the north by the Potomac River (and the Potomac's North Branch), Hampshire County is crossed by the Potomac's South Branch and the Little Cacapon and Cacapon rivers, major Potomac tributaries. Another stream, the North River, flows across Hampshire before joining the Cacapon near the Morgan County line. All flow southwest to northeast, toward the main Potomac, which is born at the confluence of the North Branch and South Branch in Hampshire County's northwest corner.

Between these river valleys stand long ridges, the most prominent being South Branch Mountain and North River Mountain. The highest point in Hampshire County, on South Branch Mountain, is about 3,200 feet above sea level, while the county's lowest elevation, where the Cacapon River crosses into Morgan County, is 510 feet. Natural features include Capon Springs, a mineral spring and resort; Caudy's Castle, a spectacular rock formation overhanging the Cacapon River; and Ice Mountain, at the base of which ice can be found year-round some years. Several protected natural areas lie within Hampshire County's boundaries, including Nathaniel Mountain and Short Mountain wildlife management areas. Other protected areas include Springfield, Edwards Run, Fort Mill Ridge, and a small portion of George Washington National Forest.

Present Hampshire County was first visited by Europeans about 1725, when explorers followed the Potomac River upstream from Harpers Ferry to the lower valley of the South Branch. Settlers were constructing homesteads by the mid-1730s. By 1748, approximately 200 people were living at Pearsall's Flats, the eventual site of Romney. In the early 1750s, Fort Pearsall was constructed nearby, protecting settlers from Indian attack and housing a school and a church.

At this time, the South Branch Valley was part of a larger estate claimed by Thomas, Sixth Lord Fairfax. According to George Washington, who worked as a young man as a surveyor for Fairfax, many of the settlers were German. Settlers lived as Fairfax's tenants, though some refused to pay the annual fees known as quitrents. The settlers found no Native inhabitants as the area was then used by tribes as a seasonal hunting ground and not for permanent occupation. Earlier, prehistoric people had lived in what is now Hampshire County, a fact evident in the large mound in Romney's Indian Mound Cemetery, probably constructed by members of the Hopewell Culture between A.D. 500 and 1000.

Hampshire was created in 1754 through an act of the Virginia General Assembly. Fairfax gave the county its name, allegedly because he thought that the hogs produced there rivaled the fine hogs of Hampshire, England. Formed from parts of Augusta and Frederick counties, Hampshire was the great mother county of the Eastern Panhandle, later providing the territory for all or part of five other West Virginia counties (Grant, Hardy, Mineral, Morgan, and Pendleton). Fairfax established the county seat of Romney, which shares credit with Shepherdstown as West Virginia's oldest incorporated town. (They were chartered the same day in 1762.) In 1777, Hampshire County encompassed approximately 2,800 square miles, on which could be found about 3,500 inhabitants. Fairfax's lands were confiscated by the state of Virginia after the Revolutionary War and redistributed to many small-tract landowners. Subsequently, the county's population increased rapidly.

The French and Indian War was the first of several conflicts to disrupt life in Hampshire County. In the mid-1750s, Indians (mostly Shawnee), encouraged by the French, attacked county settlements. Settlers either sought safety in nearby fortifications, including Fort Pearsall, Fort Cox (near the mouth of the Little Cacapon), Fort Capon (near Forks-of-Cacapon), and Fort Edwards (near present Capon Bridge), or fled eastward to the Shenandoah Valley. By the late 1750s, the colonial army had secured the county's settlement areas.

During the Revolutionary War, while most Hampshire residents supported the rebellion, some recent immigrants from England refused to raise arms against the king. A number of Tories living along the upper South Branch, including parts of present Hardy and Pendleton counties, banded together and threatened to join the British army. A nearby patriot militia quelled this uprising by overpowering the group and imprisoning its leaders.

Hampshire County figured significantly in the Civil War. While the county's westernmost section was largely pro-Union (in 1866 that section broke off and became Mineral County), most Hampshire Countians sided with the Confederacy. Divided loyalties, along with the presence of the Baltimore & Ohio Railroad at the county's northern border, rendered Hampshire a fiercely contested territory. The frequent presence of Union and Confederate troops led to continual clashing, including major skirmishes at Hanging Rocks and Blue's Gap. Romney, owing to its strategic location on the much-used Northwestern Turnpike (now U.S. 50), changed hands many times during the war, with the total number usually set at 56. In June 1866, Romney's Indian Mound Cemetery hosted one of the nation's first grave-decorating ceremonies honoring the Confederate dead. In September 1867, the same cemetery became the site of an early monument for fallen Confederate soldiers.

Romney is Hampshire's county seat and principal municipality. Points of interest include the Wilson-Woodrow-Mytinger House, built about 1770 and now the town's oldest surviving building; Literary Hall, the 1870 library and debate center for Romney's Literary Society, which was founded in 1819; and the West Virginia Schools for the Deaf and Blind (established in 1870).

Reduced in size by the creation of new counties during the 18th and 19th centuries, Hampshire County today incorporates 644.5 square miles. With a stable population of approximately 12,000 residents through the first seven decades of the 20th century, the county had a 2020 population of 23,093, up from 20,203 in 2000, and reflecting the recent trend of immigration and second-home ownership of people from the eastern megalopolis. Still largely rural, Hampshire County maintains an economy based largely upon agriculture (livestock, fruit, grain, and hay), logging and wood products, and tourism. The landscape still shows evidence of now-defunct industries, such as the iron ore furnace at Bloomery, in operation from 1833 to 1881.

In 2023, Hampshire County's largest employers were the county school system, Valley Health System, West Virginia Schools for the Deaf and Blind, the county commission, and Potomac Comprehensive Diagnostic & Guidance Center.

Two West Virginia governors, John Jeremiah Jacob (1871-77) and Herman Guy Kump (1933-37), were Hampshire County natives. Governor John Jacob Cornwell (1917-21) grew up there from the age of two and is buried in Indian Mound Cemetery. It also was the birthplace of Susan Dew Hoff (1842-1933), one of West Virginia’s first women physicians.