The starting point at the Baden end was originally Durlach, where it connects with the Rhine Valley Railway.

[2] In the 1840s, the first negotiations were held on a link between the Baden and Württemberg rail networks, connecting Karlsruhe and Stuttgart via Pforzheim, but they failed due to a disagreement on the route.

Baden saw the line as having two important tasks: on the one hand, connecting the industrial town of Pforzheim to the rail network, on the other hand, the creation of a possible direct connection between France, southern Germany and the Austrian Empire.

A treaty signed in 1850 incorporated a compromise solution that provided for the construction of the Western Railway from Stuttgart to Bruchsal, while allowing the state of Baden to build a branch line via Pforzheim to Karlsruhe.

For this reason, the Western Railway ran slightly further south that it might have in order that a junction station could be built at Eckenweiher Hof in the district of Dürrmenz.

These two valleys in the northern Black Forest were mostly in Württemberg, but could only be accessed from Pforzheim in Baden for topographical reasons.

Mühlacker did not completely lose its role as a border station until the founding of Deutsche Reichsbahn in 1920.

The line has always been an important link for international east–west traffic as part of the shortest route between Paris and Vienna.

Pairs of trains ran to/from Prague and Warsaw (via Nuremberg) and to/from Wuppertal (via Neustadt an der Weinstrasse and Bad Kreuznach).

These services needed just 52 minutes for the route from Karlsruhe to Stuttgart, with stops in Pforzheim, Mühlacker and Vaihingen.

It was envisaged at the outset that the line between Durlach and Wilferdingen would be included in order to stimulate transport between Karlsruhe and the communities of Pfinztal and Remchingen.

Even before the construction of the additional track, dual-system light rail vehicles of the Albtal-Verkehrs-Gesellschaft (Alb Valley Transport Company, AVG) began running between Karlsruhe Hauptbahnhof and Pforzheim in 1991.

The Stadtbahn track between Grötzingen and Söllingen is operated by AVG as a single-track branch line.

In long-distance transport, the Karlsruhe–Mühlacker–Stuttgart line is served every two hours by InterCity trains, stopping in Karlsruhe Hauptbahnhof, Pforzheim, Mühlacker, Vaihingen (Enz) and in the off-peak in Durlach.

On 14 December 2008 the Orient Express was replaced by a EuroNight train between Strasbourg and Vienna due to the opening of the LGV Est.

The line is also used for freight, including complete trains running from the Karlsruhe refinery to Ingolstadt.