[6] Under the Rheinschifffahrtsakte (Rhine navigation treaty) of 1831, Mainz lost its right to impose a stapelrecht (pile right, a medieval right apparently first granted by Charlemagne to some cities, including Mainz, to require river traders to unload goods in its marketplace for a specified number of days and offer them for sale or make payment in lieu) and thus its trading port and its high tariffs could be avoided.

On 13 April 1840 the Taunus Railway between Frankfurt, Mainz-Kastel and Wiesbaden was opened and took transit traffic and tourism away from Mainz.

On the other hand, Mainz was the largest city of the Grand Duchy of Hesse and was thus an attractive destination for the developing railway network.

The original Mainz station was built on land next to the Rhine outside the city wall between the Wood Tower, Fort Malakoff and today's Museum of Ancient Seafaring, and opened in August 1853.

In the course of the 19th Century the number of passengers steadily increased, as Mainz developed as the junction of lines to Darmstadt, Ludwigshafen, Aschaffenburg, Bingen and Frankfurt.

However, the terminal stations lay between the walls and the fortress and the Rhine bank, and this limited area did not permit an expansion of the railway facilities.

The Mainz architect Philipp Johann Berdellé (1838–1903) created the station's entrance building in bright Flonheim sandstone in Italian neo-Renaissance with baroque and neoclassical elements.

On both sides of the entrance reliefs (produced by the Mainz sculptors Valentin Barth and Anton Scholl) display putti at play to indicate the way for arrivals and departures: Originally the forecourt surrounded a rondel and was planted with trees, lawns and flowers.

In the course of the bombing of Mainz in World War II the Hauptbahnhof as important infrastructure was subject to several air raids.

At a cost of about € 114 million over a five-year construction period to the end of 2003, the reception building and the station hall were reconditioned and partly rebuilt.

The station is an interchange point for the Mainz tramway network, and an important bus junction for the city and region (RNN, ORN and MVG).