During the 1960s and 1970s a southward extension was proposed as the „Odenwald-Neckar-Alb-Autobahn“ (ONAA), to pass through Groß-Umstadt, Michelstadt, Schwaigern, Neckarwestheim, Mundelsheim, Berglen, Remshalden, Lichtenwald and Schlierbach, linking the ONAA to the A 8 near Kirchheim unter Teck, however the project was abandoned for ecological reasons in 1979 by the state government of Baden-Württemberg.

The A 45 branches off the A 2 at the Dortmund Nord-West intersection, passes through the eastern Ruhr area and enters the Sauerland near Hagen.

It then enters the Siegerland and the state of Hesse, where the A 45 is joined by the A 66 between the interchanges Hanauer Kreuz and Langenselbolder Dreieck.

A short stretch of road, between junctions Alzenau and Mainhausen, is on Bavarian territory, then the A 45 merges with the A 3 at the interchange Seligenstädter Dreieck in the state of Hesse, just to the west of the Bavarian city of Aschaffenburg.

The Rahmede viaduct near Lüdenscheid was closed on 2 December 2021, due to damage to its structure.