The route then runs in a northeasterly direction via Babenhausen, crosses the Main between Stockstadt and Mainaschaff and ends in Aschaffenburg.

The Rhine-Main line has the unusual distinction of being served by regional trains that operate through three German states: Rhineland-Palatinate, Hesse and Bavaria.

The basis for the construction of the line was a treaty between the Grand Duchy of Hesse and the Kingdom of Bavaria on 28 March 1852.

In February 1856, the section between Mainspitze ("Main spit" on the Rhine opposite Mainz) and Darmstadt was completed.

On 19 April 1858 the Grand Duke Louis III visited the construction site at Mainspitze and used a train.

The eastern section to Aschaffenburg was opened on 15 November 1858, with scheduled passenger trains operating on 27 December 1858.

The track is important for long distance freight transport as it bypasses the Frankfurt am Main rail node.