It branches off the A 3 at the Würzburg-West triangle and ends near the border with Switzerland.

The oldest part of the A 81 between the Weinsberg intersection (A 6) near Heilbronn and Dreieck Leonberg (A 8) near Stuttgart was finished in the years 1938 to 1940.

Instead, the A 81 shares a part of the A 8 to the Stuttgart intersection and then continues south on a motorway that was built as A 831 to Gärtringen, where it meets the original line again at a partly finished intersection.

As a result of this change of plans, Gärtringen became one of the few exits in the German autobahn network that leave to the left.

Further south, the terrain required some spectacular engineering, including a 900-metre-long (3,000 ft) bridge near Horb that spans 125 m above the Neckar river.