The line was designed by the Austrian Kingdom of Lombardy-Venetia to connect its two joint capitals and built by a company named the Imperiale Regia Privilege Strada ferrata Ferdinandea Lombardo-Veneta dell'Imperatore in honour of Ferdinand I of Austria.

On 13 January 1846 a 2-mile-long (3.2 km) bridge over the Venetian Lagoon between Mestre and Venice was opened, with 222 arches supported on 80,000 larch piles.

The line was completed with the opening of the section between Bergamo to Treviglio on 12 October 1857, following the inauguration of the bridge over the Oglio at Palazzolo.

In 1885 it became part of the Rete Adriatica (Adriatic Network) and in 1905 it was absorbed into Ferrovie dello Stato on its foundation.

The most important cities passed are Brescia, Verona, Vicenza, Padua and Mestre: these are also the key interchange points with other public transport services.