The town of Brunswick, founded in 1726, was the first permanent European settlement in what is now southeastern North Carolina. However, the story of this region has a more distant starting point. The region was initially home to the Cape Fear Indians, a group associated with the eastern Siouan tribes of North Carolina, possibly the Waccamaw. Five villages were known to have existed in 1715; the only one listed by name was Necoes located roughly where Town Creek enters the Cape Fear River in modern Brunswick County. Despite increasing tension and conflict with European settlers during the late 1600s and earlier 1700s, Cape Fear Indians served as scouts for the colonists during the Tuscarora War, but during the subsequent war in 1715, some of the Cape Fear Indians were driven from the region by a force led by Col. Maurice Moore.  Little was left of the Cape Fear Indians by 1730 and no mention is made of them after 1808.

   Permanent settlement did not come to the Cape Fear until 1726. Colonial governor George Burrington, seeking to promote growth in the area, issued land grants totaling nearly 9,000 acres in the Lower Cape Fear to a powerful group from the Goose Creek region of South Carolina, lead by Maurice Moore and his brothers Roger, Nathaniel and James. Other prominent names in the group included Allen, Porter, Moseley and Swann; all of these families were related by marriage, and were soon known simply as “the Family.” By 1725 Maurice Moore had "appropriated and laid out a certain Parcel of Land, containing Three Hundred and Twenty Acres, on the Southwest side of Cape Fear, for a Town," located approximately 18 miles from the mouth of the Cape Fear River. He named the new town Brunswick, in honor of the royal family. "The Family" quickly dominated the early landholding along the river, and in 1729 Brunswick was made the seat of New Hanover Precinct, encompassing what are roughly today New Hanover, Brunswick, Pender, Columbus, Duplin, and part of Onslow County. Around 1731, Port Brunswick was named port of entry for southeastern North Carolina.

The growing power and influence of the Family soon brought them into conflict with Governor Burrington and his successor Gabriel Johnston. Wilmington was founded in 1733 at the confluence of the Northeast Cape Fear River and the Main Branch, better protected from storms and hostile attack than Brunswick. Wilmington rapidly begin to outpace its downstream rival as a center of commerce. Governor Johnston, seeking to further hinder Brunswick and the Family, moved the county seat to Wilmington in 1740. Despite the loss of business and regional influence Brunswick continued to serve as a major port for the province of North Carolina as part of Port Brunswick, comprising both Brunswick and Wilmington. All vessels plying the waters of the Cape Fear River were required to stop first at Brunswick to pay customs duties, because the collector’s office was located at the town. Smaller vessels often proceeded up-river to Wilmington or directly to plantation docks, while the larger ships had to load and unload at Brunswick. This was because of “the Flats,” a large mud shoal formed where Town Creeks empties into the Cape Fear. Brunswick continued to serve as a port, and de facto colonial capital, with Royal Governors Author Dobbs and William Tyron residing at what is now called Russellborough.

During the later stages of King George’s War, 1744-1748, the town was raided by Spanish privateers. Many people who fled chose not to return. More harm was done in May, 1761 and September, 1769 when powerful hurricanes struck, severely damaging the town. In March of 1764 Brunswick was made the seat of the newly formed Brunswick County. Starting in November 1765 and continuing until February 1766 Port Brunswick was the center of the Stamp Act Resistance. This marked the first successful armed resistance to British authority in America.  Brunswick continued to decline heading into the American Revolution. In March, 1776 Brunswick was partially burned by Col. John Collett of the British Army, and again in May by General Lord Cornwallis. The town never recovered from these blows to the point that by the 1820s only the port facilities were in operation. By the 1840s Brunswick was a ghost town in all but name; Wilmington had fully taken over its role as primary port for the State of North Carolina.