The first part of the autobahn between Wiesbaden and the Nordwestkreuz Frankfurt, was opened as early as 1934, then called the Rhein-Main-Schnellweg.

A new section of roadway to close a second gap southwest of Fulda was opened to traffic on 13 September 2014.

[1] The section includes a 1.6-kilometre (1.0 mi) cut-and-cover tunnel and replaces a diversion which saw traffic routed onto the B 40 for approximately 9 kilometers before rejoining the A 66 just prior to the junction with the A 7; the new segment cost 154 million euros.

A portion of the Kinzig Valley Railway line was also rerouted along the new autobahn segment, which required an additional 60 million euros.

Between Zeilsheim and Eschborn the A 66 follows the course of a Roman road, which later in the Middle Ages had been given the name Elisabethenstraße, because it was part of the pilgrimage route to the grave of Elizabeth of Hungary in Marburg.