Berkeley County is located in the Eastern Panhandle. Berkeley borders Maryland to the north and Virginia to the south, with Jefferson and Morgan counties on the east and west. Its major streams are Back Creek and Opequon Creek. They drain into the Potomac River, which forms Berkeley County's northern border. The North Mountain divides the county into distinct eastern and western sections.

Berkeley originally took in all of present Berkeley and Jefferson counties and two-thirds of Morgan. It was carved off Frederick County, Virginia, in 1772. The county was named for Norborne Berkeley, a colonial governor of Virginia. Jefferson County was separated from Berkeley in 1801, and Berkeley reached its present size of 321.8 square miles when Morgan County was formed in 1820.

In the 1720s, settlers started coming into the area, which was the first part of West Virginia to be settled. Though Morgan Morgan is traditionally recognized as the first settler of European descent, several families came in the late 1720s, ahead of him. John and Isaac Vanmeter were authorized in 1730 to bring settlers to take up 40,000 acres east of Opequon Creek, and Morgan Bryant and Alexander Ross were similarly authorized for 70,000 acres west of Opequon. John Vanmeter settled in the area and took up about 3,000 acres. Many of the settlers came from Pennsylvania, New York, and New Jersey. Samuel Taylor had a ferry operating across the Potomac River southeast of Shepherdstown by 1734. Morgan acquired his 1,000 acres west of present Bunker Hill on November 12, 1735.

Much of this same land was claimed by Lord Fairfax. By 1748, Fairfax established a land office and began selling land, including some that had already been sold by Joist Hite and others. Title confusion persisted until the conclusion of a lawsuit between Hite and Fairfax, settled after both men were dead.

Many of the early settlers were Quakers, who established a meeting house by 1738 west of present Martinsburg. Presbyterians established three churches at an early date, including one at Falling Waters about 1730, one at Tuscarora in the 1740s, and the third at what is now Tomahawk by 1770. In 1743, Baptists from Maryland established a settlement and meeting house at Mill Creek, now Gerrardstown. There was also an official, state-supported Anglican Church. This was the old English Church, established at Bunker Hill about 1740 by Morgan Morgan, Dr. John Briscoe, and Jacob Hite, son of Joist Hite.

During the French and Indian War, George Washington established forts throughout Berkeley County. Several of the forts are still standing. These were homes that had stockades built to fortify them. Between the French and Indian War and the Revolution, Adam Stephen purchased 255 acres in 1770 and laid out Martinsburg, which he named after Thomas Bryan Martin, a nephew of Lord Fairfax. The town was incorporated in 1778 and became the county seat.

Berkeley County is known for its limestone and the rich valley land along its many streams. Gristmills were established in the 1730s. Flour was hauled overland to Alexandria and Baltimore and carried by boat on the Potomac River and later the C&O Canal. The coming of the Baltimore & Ohio Railroad in 1842 brought employment and a cheap means of exporting products. Later, the B&O played a big role in Berkeley County becoming part of West Virginia, since it was important that the railroad stay in Union hands.

Berkeley County was a slave-owning area, with some large plantations of 100 enslaved or more. The 1830 census listed 1,034 male enslaved and 885 female enslaved, along with 276 free Negroes, out of a total population of 10,518. Berkeley County was about 75 percent Confederate during the Civil War. Confusion remained about the status of Berkeley County and neighboring Jefferson County after the war. Both had voted to join West Virginia in 1863, but under questionable wartime conditions. Their inclusion in the new state was later confirmed by the U.S. Congress.

The Cumberland Valley Railroad, which ran from Pennsylvania to Virginia, had reached Martinsburg by 1876. Apples had been a staple fruit since the colonial period, and in the 1890s John Miller, the son of a pioneer orchardman, developed a major commercial apple industry. With the coming of electricity in 1890, Martinsburg soon became a textile town. Two major brick plants and several limestone quarries opened in the early 20th century. By 1900, the county population was 19,469. Before the Civil War, Berkeley County had had many privately owned schools. After the Civil War, free education was established, initially on a segregated basis. There are four high schools now.

Shepherd Field started in 1923 and has grown into a major airport now known as the Eastern West Virginia Regional Airport. One of West Virginia's two Air National Guard units is stationed there. The 167th Fighter Squadron, which flew Sabre jets out of Martinsburg in the late 1950s, is now the 167th Airlift Wing. Tiger Aircraft manufactured small planes near the airport from 2001 to 2006. The company bankrupted in 2007 and was succeeded by Aviation Solutions. Aero-Smith Inc. now owns the aircraft assembly plant.

In the second half of the 20th century Berkeley County became one of the fastest-growing sections of West Virginia. Major companies establishing operations there in the 1960s included 3M, General Motors, and Pet Milk, as well as the Internal Revenue Service. By 1968, Interstate 81 had been completed, crossing Berkeley County from Virginia to Maryland. In the 1970s, more industries came. A new 840-bed Veteran's Administration building replaced the Newton D. Baker Veterans Hospital. Corning Glass and DuPont Explosives established plants in Berkeley County. The population growth has been explosive, from 36,356 in 1970 to an estimated 107,098 in 2012, to 122,076 in 2020. It is now the second most populous county in the state behind Kanawha County.

Berkeley County is considered part of the Washington metropolitan area. Two large printing companies, Quad/Graphics and Quebecor Printing, have joined other major employers. In 2023, Berkeley County's top employers were the county school system, WVU Medicine, Proctor & Gamble Manufacturing, Macy’s Corporate Services, and Walmart. A big effort is being made to manage growth, maintaining something of the county's rural character, and preserving the best of its historic architecture while accommodating an expanding economy.

Notable Berkeley Countians include Morgan Morgan (1688-1766) and Gen. Adam Stephen (1718-91), surgeon and soldier. Gen. William Darke (1736-1801) had a long military career and saw much action in fighting the Indians during the French and Indian War. He voted for the ratification of the U.S. Constitution during the Virginia ratifying convention in 1788. Adm. Charles Boarman (1795-1879) served on Lake Ontario during the War of 1812, commanded the Brooklyn Navy Yard from 1852 to 1855, and remained in the U.S. Navy through the Civil War. Belle Boyd of Martinsburg was the most famous Confederate spy. Newton Diehl Baker Jr. (1871-1937) was appointed in 1916 by President Woodrow Wilson as secretary of war. Charles James Faulkner Sr. (1806-84) was appointed minister to France by President James Buchanan in 1859. He served as chief of staff to Confederate Gen. Stonewall Jackson and was awarded the rank of lieutenant colonel. Faulkner defended West Virginia's claim to Berkeley and Jefferson counties before the U.S. Supreme Court. David Hunter Strother, whose pen name was Porte Crayon, (1810-88), was one of the foremost journalists and illustrators of his day. Artist William Robinson Leigh (1866-1955) was born in the Falling Waters area of Berkeley County. Nationally recognized singer-songwriter Christian Lopez was born in Martinsburg in 1995.