The district was created in 1815, when the Prussian province of Saxony was created. The area of Lohra-Clettenberg (the former dukedom County Hohnstein) and the previously free imperial city of Nordhausen were thereafter administrated together. In 1882-3 Nordhausen left the district, which led to its renaming as the Kreis Grafschaft Hohenstein (district county of Hohenstein) in 1888. After World War II the name reverted to Landkreis Nordhausen, and in 1950 the city of Nordhausen was reincorporated into the district. In the administrative reform of 1952 several municipalities changed districts: a number were transferred from the district of Sangerhausen to that of Nordhausen, while others were transferred from Nordhausen to the districts of Worbis, Wernigerode, Sondershausen, and Sangerhausen.