In the middle of the 19th century, when Pope Pius IX decided to build a central railroad station in Rome, Via Nazionale was constructed to link the center of the city to the new station. Cardinal De' Merode, who was very actively involved in the urban works of this period, procured the land around the station, had the first buildings constructed, and the first section of Via Nazionale laid down.

Later on, after the unification of Italy, the City Council of Rome took over the project and completed it by extending the street all the way down to Piazza Venezia.
In Ancient Rome, this was Vicus Longus, the street that passed between the Viminal and Quirinal Hills to link the Baths of Diocletian with the Imperial Forums.
Via Nazionale was the first great street of the new Rome. Its imposing size and the architecture of the buildings lining it were a sign that the small, rural city of the popes had now become the capital of Italy.