The Eastern Panhandle extends for about 110 miles from the Fairfax Stone to Harpers Ferry, and is joined to the rest of West Virginia by a neck of land less than 50 miles across. Along the Morgan-Hampshire county line, the width of the state is constricted to seven miles. The panhandle includes eight counties, 3,490 square miles, and a 2020 population of 278,289, up from 261,041 in 2010—due to the growth of Berkeley and Jefferson counties. Thus, the panhandle accounts for about 15 percent of the land area of West Virginia and about 15.6 percent of the people.

While it was still part of Virginia, the present Eastern Panhandle was mostly included in the colonial lands of Lord Fairfax. The Fairfax Lands were confiscated by Virginia soon after the American Revolution, and the land titles of various tenants and purchasers remained in dispute for many years.

The panhandle took shape when West Virginia was created. Hardy, Hampshire, and Morgan counties were included in the new state to control the Baltimore & Ohio Railroad for the Union during the Civil War. Provisions were made to include Berkeley and Jefferson counties as well, but their status was not finally settled until after the Civil War. Two new counties were created within the panhandle in 1866 when Mineral and Grant split from Hampshire and Hardy counties. The panhandle also includes Pendleton County.

Except for a small wedge of territory west of the Allegheny Front, the Eastern Panhandle lies within the Ridge and Valley physiographic region. The maximum elevation is 4,861 feet, at Spruce Knob, and the minimum elevation is 247 feet near Harpers Ferry; these are the highest and lowest points in West Virginia. Mountains and ridges are frequently topped with high residual sandstone hills known as knobs, and valleys are floored with limestone and shale.

The region is drained into the Potomac River by such streams as Patterson Creek, the South Branch of the Potomac, the Cacapon River, and the Shenandoah River. Each is fed by lesser streams referred to as runs, branches, and creeks. Streams have frequently cut gaps through the northeast-southwest-trending ridges and flow through canyons or gorges such as the Trough of the South Branch, on the Hardy-Hampshire line. Before joining the Potomac, the South Branch and Cacapon rivers follow meandering courses.

The climate is characterized by cold winters and warm summers. The frost-free period is mid-April to mid-October. The prevailing winds from the west release much of their moisture as they move over the Alleghenies, and the annual rainfall is about ten inches less than the state average. Occasional storms from the Atlantic sweep across the region and cause severe flood damage, as in 1985 when 3,200 homes were destroyed and many lives lost.

Before settlement and lumbering depleted the virgin forest, oak and chestnut dominated the western and northern slopes, and pine was abundant on the hard shale soils on the southern and eastern slopes. The present forest is mixed hardwoods with a scattering of pine.

The earliest inhabitants were nomadic hunting and gathering groups. Later, Indians engaged in cultivation. When people of European descent first crossed the Blue Ridge they encountered a few Tuscarora Indians living along the Potomac River and widely dispersed lesser groups. Their legacy includes a settlement site at Old Fields, tribal battlegrounds at Packhorse Ford and Hanging Rocks, the Seneca Trail and Warrior Path, and place names such as Potomac, Cacapon, and Opequon.

John Lederer is credited as the first European-American explorer to visit the panhandle, at a point near Harpers Ferry in 1670. Settlement began in earnest after Virginia interpreted the Treaty of Albany, signed in 1722 with the Iroquois Indians, as allowing European-American settlement south of the Potomac and between the Alleghenies and the Blue Ridge. Based on tradition, the first settlement was near Bunker Hill, Berkeley County, in 1726, followed by Mecklenburg (now Shepherdstown) in 1727, Hampshire County in 1735, and Hardy County in 1744. The colonial settlers were divided among the English, German, and Scotch-Irish.

The rich limestone soils of the valleys were attractive for farming, which remains a mainstay activity. The 2017 U.S. Census of Agriculture noted 4,848 farms in the panhandle, an increase of 502 since 2007 and 2,089 since 1997. Poultry is the dominant agricultural product, though the Eastern Panhandle remains the state’s major apple producing region.

In addition to a full range of retail and service activities, others industries include food and poultry processing, and the manufacturing of clothing, machinery, chemicals, and wood products. Mineral production includes coal and gas in Grant and Mineral counties, limestone in Jefferson and Berkeley counties, and sandstone in Morgan County.

About 18 percent of the population of the panhandle lives in 21 incorporated places, including Martinsburg (2020 population of 18,773), Ranson (population of 5,433), Charles Town (population of 6,524), Keyser (population of 4,853), and others. Martinsburg is an industrial and commercial center located along Interstate 81 in Berkeley County. Petersburg (population of 2,251) is located in a basin where the South Branch River has cut Petersburg Gap through the surrounding mountains. Moorefield (population of 2,527), located in the fertile South Branch Valley, is a processing center for poultry raised in Hardy, Grant, Hampshire, and Mineral counties. More than half of the population is rural nonfarm. The expansion of Washington and Baltimore has made Berkeley and Jefferson counties the fastest-growing region of the state.

The Eastern Panhandle is arguably West Virginia's most historic region. Two events that overshadow all others are John Brown's raid on the arsenal at Harpers Ferry and the ensuing Civil War. Federal and Confederate armies repeatedly invaded the region during the war. Romney changed hands 56 times, Keyser 14 times, and Harpers Ferry (a National Historical Park since 1954) eight times.