The county was formed in 1746 from Edgecombe County. It was named for John Carteret, 2nd Earl Granville, who as heir to one of the eight original Lords Proprietors of the Province of Carolina, claimed one eighth of the land granted in the charter of 1665. The claim was established as consisting of approximately the northern half of North Carolina and this territory came to be known as the Granville District, also known as Oxford.
In 1752, parts of Granville County, Bladen County, and Johnston County were combined to form Orange County. In 1764, the eastern part of Granville County became Bute County. Finally, in 1881, parts of Granville County, Franklin County, and Warren County were combined to form Vance County.
During the late 1800s and early 1900s, Granville County played a pivotal role as tobacco supplier for the southeast United States. With many farms and contracts tied to major tobacco companies, like American Tobacco Company, Lorillard, Brown & Williamson, and Liggett Group, the local farmers became prosperous. With the Great Depression, came a plague new to the people of Granville County. The Granville Wilt Disease, as it became known, destroyed tobacco crops all across northern North Carolina. Botanists & Horticulturists found a cure for the famine at the Tobacco Research Center located in Oxford.