The land known today as Granville County was once the home of many Indian tribes, dominated mainly by the Tuscarora. After the Tuscarora War of 1711, settlers mostly from Virginia began to populate this area, attracted by the abundant game, well-watered wood, and rich land.

By 1746, the area had a population sufficiently large enough to merit becoming an independent county, separating itself from Edgecombe County's western frontier. Since most of the land in the northern half of North Carolina was part of the proprietary domain of Lord John Carteret (by title known as the Earl of Granville) the county was named Granville in his honor. Over the years, Granville yielded areas to new counties as settlements grew: Orange (1752), Bute (1764, which in turn became Franklin and Warren in 1779), and Vance (1881).

Samuel Benton was Granville County's representative to the State Assembly in 1761, when he purchased 1000 acres of land and built a plantation home known as "Oxford." In 1764, the Assembly ordered that this area be known as the county seat and Benton gave one acre of land where the courthouse was to be built. Not until 1811 did the Assembly authorize the county to buy 50 acres around the courthouse from Thomas Littlejohn and began to lay out the town, selling lots at public auction in 1812, and incorporating the town in 1816.

Through the colonial and revolutionary periods, the county was the home of a number of citizens of considerable social influence in North Carolina. Most notable was John Penn, a landowner in present day Stovall, who was elected in 1775 to be a member of the Continental Congress. He was one of North Carolina's three signers of the Declaration of Independence.

By 1860, Granville County plantations and farms had some of the state's best agriculturists, consistently growing large crops of tobacco with the help of large slave population. Oxford had become a sophisticated town and was famous as a seat of learning by the creation of several academies and colleges. Although Granville was one of five counties with as many of 10,000 slaves, there was also a sizable community of fee blacks claiming dozens of craftsmen, especially masons who helped build the grand homes of the more affluent families.

With the outbreak of the Civil War, several militia companies were formed, among them the "Granville Grays." It is estimated that over 1,500 Granville County men participated vigorously in many battles until the war's end.

The fall of the plantation economy based on slavery did not end Granville County's dependence on tobacco profits. The discovery of Bright Tobacco, which is cultivated in a sandy soil rather than rich clay soil and is "flue-dried," provided a greater incentive to cultivate the golden leaf. with the coming of railroads, tobacco warehouses and factories were built. Smaller farms with hired labor, renters, and sharecroppers increased. New towns of Stovall, Stem, and Creedmoor were created on these rail lines. Because the sand soil found in the southern townships was best suited to grow Bright Tobacco, the shift of the county's economic focus turned southwards where farm laborers migrated.

Bright Tobacco brought business to Oxford. Businessmen positioned themselves to take advantage of this new industry and many merchants, lawyers, and doctors set up shop in town. New schools, churches, literary societies, and two orphanages were formed. By the late 19th century, this thriving local economy resulted in a beautiful brick commercial district which included as many as three banks, general and hardware stores, an opera house, various professional offices, and new types of businesses.

Two world wars and the Depression brought many changes to Granville County. Even with revenues from Bright Tobacco, many Granvillians left the county for larger cities with more opportunities. The establishment of Camp Butner at the beginning of World War II engulfed many of their homes and tobacco fields, but spawned what is today a thriving community due to the various hospital and prison facilities situated in the area.

Seeing the need for attracting new industries to the county, several local business leaders formed organizations in the 1950s and 1960s to accomplish this task. By the 1980s, there were 38 major manufacturing industries in the county, principally around Oxford and Creedmoor. After more than two centuries, Granville County no longer has a primarily agricultural economy.

Even though many changes have occurred since 1746, there is a sense of tradition and place. A visitor once noted that "the people of Granville County are tops" and in 1830, an advertisement noted "The village of Oxford, in Granville County, present inducements, whether health, comfort, or pleasure equal to any in the state. It is decidedly the most beautiful village in North Carolina." Granvillians believe these descriptions of one of the oldest counties in one of the thirteen original states to still be true.