North Carolina was originally inhabited by a number of native tribes, including the Cherokee, Creek, Tuscarora, Lumbee, and Catawba. North Carolina was the first American territory the English attempted to colonize. Sir Walter Raleigh, for whom the state capital is named, chartered two colonies on the North Carolina (then Virginia) coast in the late 1580s, both ending in failure. The demise of one, the "Lost Colony" of Roanoke Island, remains one of the great mysteries of American history. Virginia Dare, the first English child to be born stateside, was born in North Carolina. Dare County is named for her.

The first permanent European settlers of North Carolina were poor English and Scots-Irish settlers who had failed at establishing themselves in Barbados. By the late seventeenth century, several permanent settlements had taken hold in the Carolina territory, which encompassed present-day South Carolina and Tennessee as well.

The Carolina territory was a gift from King Charles II of England to the so-called Lords Proprietors, a group of noblemen who had helped restore Charles to the English throne in 1660. In 1712, North Carolina became a separate colony. With the exception of the Earl Granville's holdings, it became a royal colony seventeen years later.

According to legend, on May 20, 1775, Mecklenburg County became the first North Carolina county to declare its independence from Great Britain. (No period documentation survives to verify this legend.) On April 12, 1776, the colony became the first to instruct its delegates to the Continental Congress to vote for independence from the British crown. The dates of both of these independence-related events are memorialized on the state flag and state seal.

On November 21, 1789, North Carolina ratified the Constitution to become the twelfth state in the Union.

Between the American Revolutionary War and the American Civil War, North Carolina worked to establish its state and local governments. In 1840, it completed the state capitol building in Raleigh, still standing today.

In mid-century the state's rural and commercial areas were further connected by construction of a 129 mile (208 km) wooden plank road, known as a "farmer's railroad," from Fayetteville in the east to Bethania (northwest of Winston-Salem). In 1860 North Carolina was a slave state, however according to the Museum of the Cape Fear, it was only two percent of the population that owned over 99 percent of the slaves in the state. There were also about 30,000 free blacks residing in the state.

Somewhat divided on whether to support the North or the South in the Civil War, North Carolina was the last state to secede from the Union in 1861. Governor Ellis, leader of the state at the war's beginning in 1861, famously declared in response to President Lincoln's call for 75,000 troops to suppress the "rebellion" that "you can get no troops from North Carolina." However, under his leadership and that of his successor, Governor Zebulon Baird Vance of Asheville, elected in 1862, the Tar Heel State did provide 125,000 troops to the Confederacy, more than any other Confederate state. Approximately 40,000 of those troops never returned home, dead of battlefield wounds, disease and privation.

Although few major engagements took place in North Carolina itself, her troops served in virtually all the major battles of the Army of Northern Virginia. The largest battle that occurred in North Carolina was at Bentonville, a futile attempt by Confederate Gen. Joseph Johnston to slow Union Gen. Sherman's advance into the Carolinas in the spring of 1865. Gen. Johnston surrendered one of the largest Confederate armies near Durham in late April 1865, weeks after Gen. Robert E. Lee's surrender at Appomattox, but the final surrender in North Carolina came at Waynesville in Western North Carolina in May, when remnants of Thomas' Cherokee Legion laid down their arms.