The county was formed in 1729 as New Hanover Precinct of Bath County, from Craven Precinct. It was named for the House of Hanover, which was then ruling Great Britain.
In 1734 parts of New Hanover Precinct became Bladen Precinct and Onslow Precinct. With the abolition of Bath County in 1739, all of its constituent precincts became counties.
In 1750 the northern part of New Hanover County became Duplin County. In 1764 another part of New Hanover County was combined with part of Bladen County to form Brunswick County. Finally, in 1875 the separation of northern New Hanover County to form Pender County reduced it to its present dimensions. Some of the closing battles of the American Civil War happened in the county with the Second Battle of Fort Fisher (the last major coastal stronghold of the Confederacy) and the Battle of Wilmington. The Wilmington Insurrection of 1898 and its establishment of Jim Crow laws closed out the 19th-Century with civil rights injustices which would last until the African-American Civil Rights Movement through the second half of the 20th century, three generations later. The insurrection was planned by a group of nine conspirators which included Hugh MacRae. He later donated land to New Hanover County for a park which was named for him. In the park still stands a plaque in his honor that does not mention his role in the 1898 insurrection.