[2] In 1565 it was pulled down, and a new palace was erected by Averardo Serristori, ambassador of Grand Duke of Tuscany Cosimo Medici to Pope Pius IV (r.

[2][3][4] The building became the seat of the embassy of Tuscany before this was moved to Palazzo Firenze in rione Campo Marzio, and remained property of the Serristori family until 1821.

[2] In 1867, at the eve of the happenings leading to the Battle of Mentana, Giuseppe Monti and Gaetano Tognetti, two revolutionaries fighting for the annexation of Rome to the Kingdom of Italy, placed a mine in a storeroom under the palace.

[5][6] This exploded on 22 October 1867 destroying a whole wing of the building and killing 23 Zouaves (nine of them Italians, members of the unit's musical ensemble, then soldiers under duty or punishment) and four civilians.

[8] Two years later, within the framework of the Lateran Pacts the Holy See got back the ownership of Palazzo Serristori,[3] and the school was moved there, with the financial help of Pope Pius XI and of the city of Rome.

From the school depend also the sports society "Fortitudo 1908", one of the most traditional in Rome, whose football section (whose members were nicknamed "The lions of Borgo") merged with other two clubs in 1927 to form the A.S. Roma, and the "Filodrammatica Roma", an amateur dramatic society attended by some among the best 20th century Italian actors, like Renato Rascel, Amedeo Nazzari and Andreina Pagnani.

[9] A new Latin inscription, which recites "AD CHRISTIANAM PUERORUM UTILITATE" ("For the Christian profit of the children"), coming from the destroyed school in Piazza Pia, near Castel Sant'Angelo, has been put in its place.