It is particularly important for long-distance and goods traffic because it links the Rhine-Main conurbation immediately northwest of Aschaffenburg with the Lower Franconian city of Würzburg and beyond it to the metropoles of Nuremberg and Munich.

The German name derives from the fact that it initially runs parallel to the River Main and then cuts through the Spessart hills.

During the Second World War, the Main-Spessart Railway was the target of Allied air raids as an important route for traffic.

The quadruplication of the existing line was considered, but it was not pursued due to the substandard route east of Aschaffenburg, the Spessart ramp and the narrow profile of the Schwarzkopf Tunnel.

[12] The planned new line encountered strong resistance from nature conservation associations, which feared damage to the Spessart, and was therefore abandoned by Deutsche Bundesbahn.

[13] The planning of 1982 provided for a 37.6 kilometre-long section between Aschaffenburg and Gemünden upgraded for a maximum speed of 200 km/h (with the Linienzugbeeinflussung cab signalling and train protection system).

[16] According to another source, an Aschaffenburg–Gemünden upgraded line was planned around 1982 and consisted of the Nantenbach Curve and an 18 kilometre-long bypass of the steep section to the west of the Schwarzkopf Tunnel.

[21] The Federal Transport Infrastructure Plan 1992 contained the ABS/NBS Hanau–Nantenbach/Würzburg–Iphofen project as an “urgent need” with an estimated cost of DM 1.495 billion.

The newly built section, which was opened on 19 June 2017, shortened the rail route between Würzburg and Aschaffenburg by half a kilometre.

After leaving Würzburg Hauptbahnhof, the line first passes the new port and the marshalling yard, which was closed in 2004 by the then Railion (now DB Cargo).

The line continues to follow the Main valley, where in places the very cramped right bank side is shared with the Bundesstraße 27.

In Wernfeld, it meets the tracks of the Wern Valley Railway (Werntalbahn) from Waigolshausen, although the two lines do not initially connect but run parallel.

This shortcut allows long-distance trains to use the high-speed line between Würzburg and Lohr and shortens their travel times considerably as the curvy section through the Main valley only permits moderate speeds.

From Lohr station (200 metres above sea level), the line climbed steadily for 20 kilometres to Heigenbrücken (275 m ASL) until 2017.

At the western end of the tunnel at Hofgut Wendelstein was the highest point of the line and the Heigenbrücken West operations yard, where pusher locomotives were detached and returned to Laufach.

As far as Laufach station (175 m ASL), the line ran over the Spessart Ramp, the trains on the 5.2 kilometre-long route overcame a height difference of 100 metres, corresponding to an average slope of 1.9%.

Until recently, an exception was the Saturday Intercity train pair, branded Rottaler Land, from Passau and Mühldorf to Hamburg, between Würzburg and Fulda and used the North–South railway instead of the high-speed line and stopped in Gemünden (Main).

It uses the West Rhine Railway (Linke Rheinstrecke) between Frankfurt and Cologne and runs through the Ruhr via Wuppertal in the Bergisches Land.

The section from Heigenbrücken to Aschaffenburg is located in both the Verkehrsgemeinschaft am Bayerischen Untermain (Transport association of Bavrarian Lower Main, VAB) and the transition area of the Rhein-Main-Verkehrsverbund (Rhine-Main transport association, RMV), the main fare area of which begins at Großkrotzenburg station between Aschaffenburg and Hanau.

A project called the Mottgers Link (Mottgers-Spange) involves a new line from the Frankfurt area towards Fulda and possibly towards Würzburg.

If a southern variant of this project was realised, long-distance trains between Würzburg and Frankfurt would in future bypass the Main–Spessart railway and use the Hanau–Gemünden section of the line towards Fulda.