The first settlement of the Virginia Colony in the future Clarke County was in 1736 by Thomas Fairfax, 6th Lord Fairfax of Cameron who built a home, Greenway Court, on part of his 5 million acres (20,000 km2) property, near what is now the village of White Post.

White Post was named for the large signpost pointing the way to Lord Fairfax's home.

As it lay just west of the Blue Ridge border demarcated under Governor Spotswood at Albany in 1722, the area was claimed along with the rest of the Shenandoah Valley by the Six Nations Iroquois (who had overrun it during the later Beaver Wars in around 1672), until the Treaty of Lancaster in 1744, when it was purchased from them by Governor Gooch.

Many of the early settlers of what became Clarke County were children of Tidewater planters, who settled on large land grants from Lord Fairfax.

During the American Civil War, John S. Mosby, "the Gray Ghost" of the Confederacy, raided General Philip Sheridan's supply train in the summer of 1864, in Berryville.

[3] Early in the 20th century, the future Virginia politician Harry F. Byrd Sr. and his wife established their first home near Berryville, where he undertook extensive agricultural activity growing peaches and apples.

In 1996, Forrest Pritchard revitalized Smithfield Farm by starting a grass-fed, sustainable livestock operation.

Renamed 'Smith Meadows', it is currently one of the oldest fully grass-finished farms in the United States, and its story was chronicled in the New York Times bestseller Gaining Ground.