Patriots who defied the Crown in the Revolution were led by William Hooper, a signer of the Declaration of Independence. In 1765, eight years before the Boston Tea Party, the citizens of Wilmington kept the British from unloading their stamps for the Stamp Act. In 1781, Cornwallis held the town as his main base of operation for almost a year. After the battle of Guilford Courthouse, the Lord General came back to Wilmington before heading for Yorktown and defeat.

During the Civil War, blockade runners brought fortunes in goods past Federal ships lying off Cape Fear, making Wilmington the Confederacy's chief port until January 1865, when it fell. Wilmington was North Carolina's biggest town until 1910, when railroad-fed industries of the inland Piedmont area outgrew the limited facilities of the harbor. The channel, harbor, and expanded port facilities bring goods from throughout the world to the area.