In 1797 Johann Wolfgang von Goethe passed on this busy road from Weimar via Tuttlingen to Switzerland.

The construction of the main railways of Württemberg from 1844 to 1850 meant that the Swiss postal road lost its significance and Tuttlingen no longer had a convenient location.

The line to Tuttlingen was opened on 15 July 1869, connecting it to the railway network the first time, restoring the convenient position it had lost two decades ago.

The first Tuttlingen station was located near the current roundabout at Aesculap-Platz, at the intersection of federal highways 14 and 311 just outside the settlement and off the road network at the time.

The line follows the Prim, the Faulenbach and the Elta rivers from Rottweil to the south and passes west of Tuttlingen to reach the valley of the Danube to connect with the Black Forest Railway at Immendingen station.

The construction of Bahnhofstraße required the straightening of the Danube, which originally flowed in the area of present-day Stadtgarten (town park).

The connection to the railway was also one of the reasons for the strong growth of Tuttlingen, which now extends mainly to the west towards the station.

The rail connection played an important role in the industrial development of Tuttlingen; it had previously been based largely on agriculture and trade.

Tuttlingen was not yet connected to the east by rail: the initial section of the Danube Valley Railway (Donautalbahn) from Ulm, completed in 1873, only extended as far as Sigmaringen.

Further construction, starting in 1887 only under pressure from the German General Staff, extended the line to Tuttlingen for strategic military purposes.

For economic reasons, Württemberg was interested in ensuring that the traffic from Berlin to Switzerland ran through its territory and not only through the neighbouring states of Bavaria and Baden.

Württemberg sought to upgrade its part of the railway line from Berlin to Zurich via Würzburg, Stuttgart and Tuttlingen.

To this end, it entered into an agreement with Deutsche Reichsbahn on 23 February 1927, which resulted in several upgrading projects, including the construction of a new station in Tuttlingen.

An average of 280 workers found employment daily at Tuttlingen station during the 1928–1933 construction period, representing a huge relief for the local labour market, which had been battered by the global economic crisis.

Overall, the new station required 20,000 m³ of concrete and 900 tons of steel and led to the building of 24.6 kilometres of track.

The west wing of the station building, the freight yard, the locomotive depot and the railway tracks were damaged severely.

In 1946, the French occupation forces removed as reparations one of the tracks of the Gäu Railway between Tuttlingen and Horb am Neckar, which had been duplicated only a few years earlier.

Also in 1992, DB sold the west wing of the station building to an insurance broker, who then renovated it and rented part of it.

Large parts of the station and the railway facilities are now privately owned and are no longer used to serve rail services.

Tuttlingen is served by a total of seven pairs of trains per day that connect directly to Zurich and another eight that provide interchange in Singen, producing an hourly service.

The international IC trains consist of class 1016 or 1116 locomotives of the ÖBB and EC coaches provided by the SBB, while the domestic German connections are operated with Intercity 2 sets.

Between May and October, Tuttlingen is served by the Naturpark-Express, connecting Tuttlingen with the Upper Danube Nature Park (Naturpark Obere Donau) and Gammertingen with connections to the RadWanderShuttle to Engstingen in the east and in the west with Blumberg on the Wutach Valley Railway museum railway and is targeted primarily at the tourist market.

Since Tuttlingen station is well outside the city centre and major residential areas, many passengers will need to use buses to continue their journeys.

Immediately east of the station is the Danube cycle path (Donauradweg), which is a major tourist attraction.

Rather, cyclists must cross Aesculap-Platz, the intersection point of two busy highways to reach the city centre.