The Oker River enters the district in the south, runs through the city of Wolfenbüttel (the district seat), and exits to the northwest.
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.