It was mentioned in 1118 as Wulferisbuttle, when the Saxon count Widekind of Wolfenbüttel erected a water castle on the important trade route from Brunswick to Halberstadt and Leipzig.

Devastated in the 1542 Schmalkaldic War, it was largely rebuilt in a Renaissance style under Duke Julius of Brunswick-Lüneburg, including several gracht waterways laid out by Hans Vredeman de Vries.

The duke vested the citizens with market rights in 1570 and founded the Ducal Library (Herzogliche Bibliothek, the later Bibliotheca Augusta) two years later.

In June 1641 the Battle of Wolfenbüttel was fought here, when the Swedish forces under Wrangel and the Count of Königsmark defeated the Austrians under Archduke Leopold of Habsburg, however, they failed to occupy the town.

[11] Victims include Marguerite Bervoets and Fernande Volral, and a Dom Lambert, a monk of Ligugé Abbey in France, who was beheaded there on 3 December 1943.

Today, Wolfenbüttel is smaller than the neighbouring cities of Braunschweig (Brunswick), Salzgitter, and Wolfsburg, but, because it was largely undamaged by the war, its downtown is rich in half-timber buildings, many dating several centuries back, and it still retains its historical character.

Wolfenbüttel is home of several departments of the Ostfalia University of Applied Sciences[15] and the Lessing-Akademie [de], an organisation for the study of Lessing's works.

Beginning in 2009 the Landesmusikakademie Niedersachsen is located in the Seeliger Park and sponsored by the state of Lower Saxony to promote music education at various levels.