Accomack County was named for the Accomac Indians, who lived on the Eastern Shore at the time of the first English settlement in Virginia. The word means "on-the-other-side-of-water place" or "across the water." It was one of the original eight shires, or counties, first enumerated in 1634 and spelled Accomac without the k. The county's name was changed to Northampton County in 1643. The present county was formed from Northampton about 1663. In October 1670, the General Assembly temporarily reunited Accomack and Northampton Counties as Northampton County. In November 1673, Accomack County was again separated from Northampton. In early records, the county's name was spelled many ways. In 1940 the General Assembly adopted the present spelling, Accomack. The county gained a small part of the southern end of Smith's Island from Somerset County, Maryland, in 1879, after the United States had approved boundary changes between Virginia and Maryland that had been agreed to in 1877. The county seat is Accomac.

In 1806, the General Assembly passed a law stating that all emancipated enslaved people, freed after May 1, 1806, were required to leave the Commonwealth. Those who remained in the Commonwealth more than a year could be put on trial by the state, and if found guilty, would forfeit their right to freedom and be sold with the proceeds from the sale going to the state treasury.