The Hessian Ludwig Railway received a concession from the Grand Duchy of Hesse to build the 31 km southern section of the line through the Grand Duchy of Baden on 3 August 1875; the Baden section of the line was authorised by a treaty between the two grand duchies that had been signed on 3 August 1874.Because the line had to overcome the topography over the watershed between the Main and Neckar, many engineering structures were required between Erbach and Eberbach, including the Himbächel Viaduct and the Krähberg Tunnel, as well as gradients of 1 in 70.
The line was opened to Ober-Ramstadt on 28 December 1870, to Reinheim on and to Wiebelbach-Heubach two months later.
On 23 December 1871 the section to Erbach was opened, having been delayed by a collapse in the Frau-Nauses tunnel.
Originally, it had been planned to complete the line in 1879, coinciding with the opening of the Neckar Valley Railway from Neckargemünd to the Jagst river, but due to the stretched financial situation of the Hessian Ludwig Railway Company, this schedule could not be met.
Passenger trains took two hours to run over the 56 km route between Darmstadt and Erbach in 1871.
On 1 March 1882, the 23 km long Erbach–Hetzbach section running through the Krähberg Tunnel was opened.
On 27 May, this was followed by the opening of the last section from Eberbach to Hetzbach, first for passenger traffic and five days later for freight, making the Odenwald Railway operable along its entire length.
At several stations (Darmstadt Ost, Ober-Ramstadt, Reinheim, Wiebelsbach, Groß-Umstadt) access to the trains were improved with new platforms.
In Darmstadt Nord, a new track connection was built allowing a direct journey to Frankfurt over the Main-Neckar Railway and a new station was opened at the new campus of the Technical University of Darmstadt, called Darmstadt TU-Lichtwiese.
The locomotive-hauled trains often ran as push-pull trains. Through passenger services between Frankfurt and Stuttgart were terminated in December 2004 when Baden-Württemberg refused to support them.
Passenger trains on the 56 km route between Darmstadt and Erbach took 1 hour and 17 minutes in 1982; in 2004 they took 1 hour and 10 minutes, which corresponded to an average speed of 48 km/h.
A number of additions and connections to different lines were connected to the Odenwald Railway over the years: From 1925 the Odenwald Railway was served by local services as well as three “hedgerow expresses” (Heckeneilzug), from Frankfurt via Hanau, Erbach and Eberbach, connecting with Stuttgart and during some timetable periods in the 1980s even corridor express (D-Zug) trains.