It was part of the former Baden Oldenwald Railway from Heidelberg to Würzburg, and thus a main line, which is why its trackbed was built for two tracks.

The best route in terms of topography was along the Neckar valley to the town of Eberbach, but this was ruled out because it ran through the Grand Duchy of Hesse.

The lack of sufficient funds and the outbreak of the Second Italian War of Independence in northern Italy created a crisis for the project, even bringing construction to a standstill between 18 April and 20 October 1859.

Traffic volume remained lower than expected, especially after 24 May 1879, when the Neckar Valley Railway opened on the Neckargemünd–Neckarsteinach–Eberbach–Neckarelz–Mosbach route, converting the Meckenheim–Neckarelz section into a de facto branch line in the following years, as trains on the Heidelberg–Würzburg route preferred to use the gentler Neckar Valley Railway.

Prisoners provided forced labour to an Obrigheim supplier of materials for a planned underground weapons factory with the code name of Goldfisch ("gold fish").

On 30 March 1945, German troops retreating to the southeast blew up the Neckarelz railway bridge to impede the advance of the Allies, as it was the only permanent river crossing on a long section of the Neckar.

After World War II the newly founded Deutsche Bundesbahn operated the remaining line between Meckesheim and Obrigheim.

Because of the maintenance costs, the Federal Ministry of Transport on 10 May 1971 authorised the closure for all traffic of the Aglasterhausen–Obrigheim section with its two tunnels, which was implemented at the timetable change of 25 September 1971.

On 1 January 1982 the state-owned South-West German Railway Company (Südwestdeutsche Eisenbahn-Gesellschaft, SWEG) took over the line from Deutsche Bundesbahn under a 20-year lease.

The Krebsbach Valley Railway from Neckarbischofsheim Nord to Hüffenhardt, which the government planned to close, was also operated by the SWEG.

It was originally planned to start Rhine-Neckar S-Bahn operations with class 425 electric multiple units of the new S 51 service on the Schwarzbach Valley Railway on 14 December 2009.