The district was created in 1832 when the Duchy of Brunswick was subdivided into six districts. It remained unchanged until 1941 when the Salzgitter-Verordnung ("Salzgitter Ordinance" creating the city of Salzgitter) took effect and removed 20 municipalities from the district; in return, 10 municipalities from the (then) District of Marienburg were turned over to Wolfenbüttel. When the district boundaries changed again in 1974 (as part of administrative reforms), parts of the former District of Brunswick were added to Wolfenbüttel. Additionally, several municipalities—most notably the city Bad Harzburg—were exchanged with the neighboring District of Goslar.
The lion at the top of the coat of arms represents the House of Welf, the ruling house of the Duchy of Brunswick from the 13th century. The ears in the bottom symbolise the district's mostly agricultural character.