By that time railways were proliferating even in the Piedmont; in 1859 when Austria declared war on Sardinia the Piedmontese and Austrian networks had come close to the point where the bridge over the Ticino was subsequently built connecting Turin and Milan.

The Treaty of Zürich signed on 10 November 1859 also included an agreement[7] that was the origin of the Società delle Strade Ferrate della Lombardia e dell'Italia Centrale (Lombardy and Central Italy Railway Company) and the Società delle Strade Ferrate dell'Austria meridionale e del Veneto (Southern Austria and Veneto Railway Company).

The construction of a long steel girder bridge, completed in 1864, put an end to the insecurity of the rail link.

The Società delle Strade Ferrate della Lombardia e dell'Italia Centrale was merged with other Alpine and Apennine lines, becoming the Società per le strade ferrate dell'Alta Italia ("Upper Italian Railway", SFAI) with 2,092 km of lines in operation and 300 km under construction or proposed.

In 1871 with the opening of the Fréjus Rail Tunnel to rail traffic,[10] a mail train, the Indian Mail (known in Italian as La Valigia delle Indie) was routed over the line from Piacenza to Bologna; it operated weekly from London and Paris via Modane and Turin to Ancona and Brindisi, where it connected with steamships to India via the Suez Canal.

In 1879 this became a passenger train, and later carriages were branded "CIWL" (Compagnie Internationale des Wagons-Lits) by agreement with the operator of the line, the SFAI.

The reorganisation of the Italian railways into four companies, however, gave rise to more problems than it solved, so in 1885 the railways were divided between two new companies, the Società per le Strade Ferrate del Mediterraneo — known as the Rete Mediterranea (Mediterranean Network) and comprising the lines west of Milan and on the Tyrrhenian coast, and the railways of Calabria and Basilicata — and the Società Italiana per le strade ferrate meridionali—known as the Rete Adriatica (Adriatic Network), comprising the remaining lines.

These networks connected at various stations: Milan, Pavia, Piacenza, Parma, Pisa, Florence, Rome, Naples and Taranto.

Starting in 1890 the Adriatic Network agreed to the luxurious Peninsular and Oriental Express from London to Brindisi[11] operating on the line at up to 80 km/h.

The line between Milan to Piacenza was originally not used much, except for local traffic; most travellers preferred to take direct trains between the "capitals" of Turin, Florence and Rome.

The successful experiment was followed in 1928 by the equipping of the line to Bologna for the repetition of two types of signals: stop and go; if the driver did not comply the braking system would be automatically applied.

During the same period the ever-increasing traffic on the line, which had become the primary axis of the Italian railway network, began to saturate the capacity of the stations in Bologna, and a rail bypass was built to its north.

Following the electrification of the line in 1938, Minucciani's system of in-cab signalling was abandoned because it was considered too expensive to equip the electric locomotives with it.

Although these tests were successful it was not implemented because investment in that period prioritized the speed and punctuality of trains for propaganda reasons rather than innovation in safety devices.

In 2002, work began on the construction of the Milan–Bologna high-speed railway, which connects to the old line in the municipality of San Zenone al Lambro.

After Piacenza the railway runs parallel to the Via Emilia (state highway 9) passing through Pontenure, Cadeo, Fiorenzuola d'Arda and Alseno.

[18] After Castelfranco Emilia, the railway enters the Metropolitan City of Bologna, which includes the stations of Samoggia and Anzola dell'Emilia.