The Northern Panhandle began to take shape in 1779 when Pennsylvania and Virginia agreed that their boundary would be the Mason-Dixon Line extended due west five degrees, and then straight north to the Ohio River. In 1784 Virginia ceded all its territory north and west of the Ohio to the United States, making the river Virginia's western boundary. Virginia retained control of the 585 square miles between the borders of Pennsylvania and the Ohio River. This long sliver of territory, extending 64 miles to an apex at Chester, became the northernmost part of West Virginia when our state was created in 1863. Near New Cumberland and Follansbee, the panhandle is only four miles wide.

The panhandle is a part of the Allegheny Plateau and slopes westward from a maximum elevation of about 1,400 feet down to the Ohio River. At Chester the river is about 660 feet above sea level, and about 620 feet at New Martinsville near the base of the panhandle. The plateau is drained to the Ohio by creeks that include Grave, Wheeling, Kings, Harmon, Buffalo, Fish, and Cross. The Ohio River and its flood plain are the most conspicuous physical features. Other interesting physical features include the Narrows, McColloch's Leap, and the river islands. The climate of the Northern Panhandle is humid, with cold winters and warm summers.

Before railroads the Ohio River was the major transportation artery. Flatboats, keelboats, and steamboats were built and launched along the river, especially at Wheeling. Ohio River navigation remains important and is maintained by a system of modern locks and dams, of which two are located at New Cumberland and Pike Island.

Humans were living in the Northern Panhandle region as early as 7000 B.C. and probably earlier. Grave Creek Mound at Moundsville, the largest of its kind in the country, is the panhandle's most important prehistoric feature. The mound was built in the Adena period, probably between 400 and 200 B.C. By the time of European-American colonization, the Indians who had followed their mound-building ancestors were sparse and mainly members of the Delaware tribe.

By 1769, the frontier had reached the upper Ohio. The Wetzels settled in present Marshall County, and the Zane brothers arrived at Wheeling. During the American Revolution, Fort Henry, near the mouth of Wheeling Creek at present Wheeling, withstood a two-day siege by 300 British and Indians in 1782. Eight decades later, much of the leadership in establishing the state of West Virginia came from the Northern Panhandle. Wheeling was the state capital from 1863 to 1870, and from 1875 to 1885.

The early settlers derived their livelihood from agriculture, but industry was the region's future. An abundant resource base included coal, iron ore, petroleum and natural gas, timber, clay, and glass sand, while the National Road, Ohio River, and the later railroad provided transportation.

The Northern Panhandle is an urban-industrial region important in the production of glass, pottery, iron and steel, chemicals, petroleum and natural gas, and coal. According to the 2020 census, the Northern Panhandle’s population was 124,670, a 5.8 percent decrease from 2010. This comprises about seven percent of West Virginia’s total population. Nearly 44 percent of the panhandle's residents live in Wheeling, Weirton, and Moundsville.

Chester and Newell began as pottery towns using clay dug from nearby hills. New Cumberland, the county seat of Hancock County, was famous for brickyards and pottery works. The first iron furnace west of the Alleghenies was located at a site on Kings Creek in 1794, and in 1909 Weirton was founded when the Weirton Steel company began production at the site on the Ohio River. For two decades after 1984 Weirton Steel was the largest employee-owned steel firm in the United States.

Wellsburg, settled in 1772, is the county seat of Brooke County and was the site of the first glass plant (1813) in present West Virginia. The city continues to make hand-crafted glass. Bethany College at Bethany is the oldest degree-granting college in the state. Follansbee and Beech Bottom were steel towns on the Ohio River.

Wheeling, the county seat of Ohio County, is the regional hub and premier manufacturing city. Flour milling, tobacco, iron and steel, boat building, pottery and glass, and chemicals have been important in the economy of Wheeling. Other Ohio County towns include Bethlehem, Triadelphia, Clearview, and Valley Grove, as well as West Liberty, which is the location of West Liberty State University, chartered as a private academy in 1837.

Moundsville, named after the prehistoric burial mound at the mouth of Grave Creek, is the county seat of Marshall and site of the state penitentiary from 1866 to 1995. Other Marshall County towns include Benwood, Cameron, Glen Dale, and McMechen.

In recent years the Northern Panhandle has become an attractive tourist region. The attractions include Oglebay Park, the Winter Festival of Lights at Oglebay, the Wheeling Suspension Bridge, the Palace of Gold at New Vrindaban, the Grave Creek Mound, West Virginia Independence Hall, Wheeling Island Hotel, Casino & Racetrack, and Mountaineer Casino, Racetrack & Resort.