Local Native American groups had lived in the Hillsborough area for thousands of years by the time Spanish explorers entered the region.

The Great Indian Trading Path, used by generations of Native Americans, crossed the Eno River in this area.

Historic Siouan-language tribes such as the Occaneechi and the Eno were living in the Hillsborough area at the time of European contact.

The English explorer John Lawson recorded visiting "Occaneechi Town" here when he traveled through North Carolina in 1701.

It was renamed in 1759 as Childsburgh (in honor of Thomas Child, the attorney general for North Carolina from 1751 to 1760 and another of Granville's land agents).

[8] Hillsborough was an early Piedmont colonial town where court was held, and was the scene of some pre-Revolutionary War tensions.

In the late 1760s, tensions between Piedmont farmers and county officers arose in the Regulator movement, which had its strongest support in Hillsborough.

[9] With specie scarce, many inland farmers found themselves unable to pay their taxes and resented the consequent seizure of their property.

Ultimately, the frustrated farmers took to arms and closed the court in Hillsborough, dragging those they considered corrupt officials through the streets.

[9] Tryon and North Carolina militia troops marched to the region and defeated the Regulators at the Battle of Alamance in May 1771.

The North Carolina Provincial Congress met in Hillsborough from August 20 – September 10, 1775, at the outset of the American Revolution.

With the hope of effecting the incorporation of a Bill of Rights into the frame of government, delegates voted (184–84) to neither ratify nor reject the Constitution.

During the bicentennial celebration of the writing and ratification of the Constitution, a historical marker was placed at the site (now the Hillsborough Presbyterian Church) commemorating the convention.

In March 1865, Confederate General Joseph E. Johnston and his troops wintered just outside Hillsborough at the Alexander Dickson home.

More than 100 surviving late eighteenth and nineteenth-century structures help illustrate its history of prominence in the early period of the state.

In addition, numerous secondary buildings, bridges, mill sites and dams along the Eno River document the local history.

The Old Orange County Courthouse is an 1844 Greek-revival building designed and built by local builder John Berry.

The circa 1760s Hillsborough Clock located atop the town courthouse was a once believed to be a gift from King George III, but its origin is currently unknown.

Notable eighteenth-century owners include General Thomas Person, Peter Malett, William Duffy, and John Taylor, who was clerk of the Superior Court from 1800 to 1845.

It is believed that Peter Brown Ruffin, a landowner and employer to the west of Hillsborough, bought the two 1-acre (0.40 ha) lots that comprise the cemetery from the town in 1854 to use as a burial ground.

[15] A former house once owned by Julian Carr named Poplar Hill is located in the town's historic district.

For its size, Hillsborough has a high concentration of residents who are nationally known artists and authors, including Lee Smith, Jill McCorkle, Allan Gurganus, Michael Malone, Annie Dillard, Hal Crowther, Frances Mayes, and David Payne.