Although Morgan Morgan is often recognized as the first European settler in present Berkeley County, several families arrived before him in the late 1720s. In 1730, John and Isaac Vanmeter were granted 40,000 acres east of Opequon Creek, and Morgan Bryant and Alexander Ross were granted 70,000 acres west of it. John Vanmeter settled in the area and took about 3,000 acres. Many settlers came from Pennsylvania, New York, and New Jersey. Morgan Morgan acquired his land near Bunker Hill in 1735.

Joist Hite, originally Hans Jöst Heydt, was a pioneer and land speculator who emigrated from Germany. He led 16 German and Dutch families to America. By 1731, he had moved to the Shenandoah Valley and received a 100,000-acre land grant from Virginia. Hite is credited with starting the first settlement on Opequon Creek in Berkeley County.

Many early settlers here were Quakers, who built a meeting house by 1738. Presbyterians set up churches in the 1730s and 1740s, and Baptists from Maryland established a settlement at Mill Creek (now Gerrardstown) in 1743. An Anglican Church was also founded at Bunker Hill around 1740.

During the French and Indian War, George Washington built forts in the county. In 1770, Adam Stephen created Martinsburg, which became the county seat in 1778.

The county is known for its limestone and fertile land. Gristmills started in the 1730s, and products like flour were shipped by land and river. The arrival of the Baltimore & Ohio Railroad in 1842 helped the county grow and played a key role in its joining West Virginia.

Berkeley County had large plantations, and by 1830, there were over 1,000 enslaved men and 885 enslaved women. The total population was around 10,500, with a small number of free African Americans.