The Ruhr-Sieg-Express runs daily every hour and utilises four railway lines built by the Bergisch-Märkische Railway Company: There are plans, with the introduction of the Rhine-Ruhr Express (RRX) network commenced in 2020, for the Ruhr-Sieg-Express and the Ruhr-Lenne-Bahn services to run between Essen and Bochum on the S-Bahn route via Wattenscheid-Höntrop instead of on the main line via Wattenscheid.

The Ruhr-Sieg-Express is operated under the integrated regular-interval timetable of North Rhine-Westphalia, called NRW-Takt, under which trains arrive at major interchange stations at roughly the same time in order to facilitate transfers.

In Siegen, the Ruhr-Sieg-Express has regular-interval connections with the Rhein-Sieg-Express (RE 9) towards Cologne, the Sieg-Dill-Bahn (RB 95) to Au (Sieg) and Dillenburg, as well as the Main-Sieg-Express (RE 99) to Gießen, continuing every two hours to Frankfurt.

Coming from Siegen/Iserlohn on the RE 16, it is possible to change in Hagen to the Volmetal-Bahn (RB 52) to Dortmund and Lüdenscheid, the Maas-Wupper-Express (RE 13) to Hamm and Venlo, the Sauerland-Express (RE 17) to Warburg and long-distance services to Bremen/Hamburg and Hannover/Leipzig.

In the early days of the Ruhr-Sieg-Express it was mainly operated with class 425 electric multiple units, but later the rolling stock used varied considerably.

The use of both classes ended at the timetable change on 9 December 2007, when Abellio Rail NRW took over operations on the line with two-and three-part Stadler FLIRT EMUs.