Milano Centrale has high-speed connections to Turin in the west, Venice via Verona in the east and on the north–south mainline to Bologna, Rome, Naples and Salerno.

The Simplon and Gotthard railway lines connect Milano Centrale to Basel and Geneva via Domodossola and Zürich via Chiasso in Switzerland.

The Milan suburban railway service, however, does not use Milano Centrale but the other mainline stations: Porta Garibaldi (northwest), Cadorna (west) and Rogoredo (east).

Architect Aldo Rossi declared in an interview of February 1995 to Cecilia Bolognesi:[5] "They told me that when Frank Lloyd Wright came to Milan, and he came only once, he was really impressed by it and said it was the most beautiful station in the world.

The last, real, contest for its construction was won in 1912 by architect Ulisse Stacchini, who titled his project "In Motu Vita," meaning "Life in Motion" in Latin.

Stacchini made multiple revisions to the project, mainly to quell concerns by the Milan city government about high construction costs.

[16] There remain unrestored and inaccessible areas to the public within the station, including a waiting room with swastikas on the floor designed to receive Adolf Hitler.

Daily international destinations include Basel, Lugano, Geneva, Zürich, Paris, Vienna, Marseille and Munich.

All SBB-CFF-FSS Eurocity (operates by Trenitalia in Italy) now save 35 minutes of total journey time between Bellinzona and Arth-Goldau.

[18][20] The station, along with Roma Termini and Firenze Santa Maria Novella, has security gates, normally free flowing, though supervised by agents.

On the northern side of the railway yard, there used to be a loop curve so that trains could turn around and reverse back into the station.