[6] The city was named in honor of former North Carolina Supreme Court Chief Justice Leonard Henderson, who lived nearby and was a friend of early settler Lewis Reavis.

Henderson was officially chartered by the North Carolina General Assembly in 1841.

[7] Ashland, Henderson Central Business Historic District, Henderson Fire Station and Municipal Building, Library and Laboratory Building-Henderson Institute, Mistletoe Villa, Maria Parham Hospital, Daniel Stone Plank House, Vance County Courthouse, West End School, Zollicoffer's Law Office, and Barker House are listed on the National Register of Historic Places.

As of the 2020 United States census, there were 15,060 people, 5,715 households, and 3,549 families residing in the city.

The city was last served by passenger rail in 1986, at which time Amtrak's long-distance Silver Star was re-routed through Rocky Mount and part of the S-Line was abandoned.

[14] Restoration of the line is planned as part of the Southeast High Speed Rail Corridor project.