Located in the northern Coastal Plain along the Virginia border, Northampton County was formed in 1741 from a division of Bertie County after settlers migrated to this part of the Albemarle precinct in the early eighteenth century.

Hertford County lies to the east, Bertie County to the south, Halifax County to the south and west, and Warren County to the west. The Roanoke River runs northwest to southwest along the southern border of the county, and the Meherrin River forms a portion of the eastern boundary. These two navigable rivers have been instrumental in the social and economic development of the county, influencing settlement and transportation patterns.

The county seat was established in roughly the center of the county and was known originally as Northampton Courthouse. When the community was incorporated in 1823, the county seat was renamed Jackson in honor of Andrew Jackson.