At the end of the 1840s, the Kingdom of Württemberg wanted to connect its railway lines with those of Grand Duchy of Baden, from Heilbronn via Sinsheim either to Wiesloch or Heidelberg.

[1] As part of this process, it was determined on 27 April 1860 that the section from Heidelberg via Meckesheim to Mosbach would be built at government expense.

[1] There was a derailment on the first day of operations on the Neckar bridge at Neckarelz due to a landslide as a result of heavy rain.

[1] The second track from Heidelberg Karlstor to Meckesheim was opened in mid 1869,[1] because with the lines to Bavaria and Württemberg significantly more trains would run on this section.

[1] In the Second World War, on 2 February 1945, the Neckar bridge between Bad Wimpfen and Jagstfeld was severely damaged by bombs and as a result the line from the 35.52 kilometre point was abandoned in 1952.

[3] The halt of Bad Wimpfen Neckarbrücke was built as a workaround near a ferry to the other side of the Neckar, not far from Jagstfeld station, on 5 October 1947.

[1] The level crossing over Horrenberger Straße in Zuzenhausen (guard post 3a) receives a locomotive-monitored flashing light system on 6 June 1969.

A project entitled "Electrification and expansion of the transport infrastructure on the Elsenz Valley Railway and the Schwarzbach Valley Railway", included, in addition to the electrification, the reconstruction or conversion of all platforms and the modernisation of the stations from Neckargemünd to meet the standards of the Rhine Neckar S-Bahn, including, among other things, bringing platform heights to 76 centimetres.

[3][7] This now remotely controls the entire line, along with the branches to Aglasterhausen and Eppingen, via the signalling computers at Waibstadt, Sinsheim, Grombach and Bad Rappenau and is operated by the Meckesheim 1 (up to and including Sinsheim Hbf) and Meckesheim 2 dispatchers at the Karlsruhe operation centre.

The monitoring of the two remote-controlled level crossings in Mauer and south of Reilsheim was transferred to the electronic interlocking on 3 February 2009.

In December 2012, a retaining wall collapsed at Bad Wimpfen, causing this section of the line to be closed for three months.

[5] These stopped, in addition to the places served by the other trains, at the halts of Heidelberg Peterskirche, Jägerhaus-Wolfsbrunnen, Kümmerlbacher Hof, Waldhilsbach and Reilsheim that were established at the same time.

[1] From the summer of 1973 to 1975, there were through coaches from Paris to Heilbronn, which formed part of the semi-fast trains 1555 and 1756 on the Elsenz Valley Railway.

Initially, individual local trains were operated by the SWEG with class NE 81 diesel multiple units.

[3][10] At the timetable change in June 1997, services running later at night were introduced and the last train from Heidelberg to Sinsheim then ran around 22:12.

[1] From 28 September 1997, Regional-Express services were operated with class 611 diesel multiple units,[3] which shortened travel times as a result of their tilting technology.

[1] Up to December 2014, the RB 74 Regionalbahn service ran from Sinsheim to Bad Friedrichshall (some continuing to Heilbronn) every hour.

[1] Thus, at this time one RE service ran each direction every hour, although the additional trains could not stop in Meckesheim because of lack of line capacity.

At this time a rail replacement bus service ran between Bad Rappenau and Neckarsulm, which was extended to Sinsheim on weekends.

As a result of the division of the S-Bahn network into various lots for the re-tendering of operations, S 5 services no longer continue to Kaiserslautern as line S 2 on Sundays and public holidays.

[17][18] The introduction of the northern line of the Heilbronn Stadtbahn and construction work for the S-Bahn network increased disturbances, which reduced punctuality and trains were often terminated in Steinsfurt or Neckargemünd.

[16][17] As part of the MORA C [de] concept (Market-oriented offer for Cargo), the last freight operations at Meckesheim were abandoned on 31 December 2001, but, until 2009, freight wagons that were loaded on the Schwarzbach Valley Railway and the Krebsbach Valley Railway carried timber to Mannheim twice a week.

[19] Since the upgrade of the line for S-Bahn operations, as a result of which only 3 tracks are available in Meckesheim, and the provisional closing of the Krebsbach Valley Railway in 2009, these timber trains no longer run.

Freight trains regularly run from Heilbronn to the Bad Wimpfen Solvay chemical works.