In 1567, the construction work on the residential complex began. Marco Sittico Altemps commissioned architect Martino Longhi il Vecchio the extension of the previous complex of Villa of the Quintilii. Immediately after, Pope Gregory XIII took up permanent residence here. It was actually in the villa that the papal bull Inter Gravissimas was proclaimed from which the Gregorian Calendar originates.

Between 1616 and 1618 the villa was extended by the Flemish architect Jan Van Santen (Giovanni Vasanzio), the brilliant designer of the Retirata, the Giardino Grande, the Teatro delle Acque with the Fontana dei Draghi in the centre, and the great quadrangular courtyards inspired by the cour d’honneur, residence of French royalties.

During the 17th century, it became property of the Borghese family and thanks to Cardinal Scipione Borghese, Villa Mondragone riched its maximum splendour. Many popes stayed here including Clement VIII, Paul V and Urban VIII who left Monteporzio to go to Castel Gandolfo in 1626. In 1858, George Sand was a guest at the villa where he found a suitable atmosphere for the setting of his romance La Daniella.

In 1866, the complex was purchased by the Jesuits and became first the Ghislieri College, and later (until 1953) the Noble College of Mondragone, high prestige boarding school for young aristocrats. Under the administration of the Jesuit Fathers the Villa, which had become a famous school of scientific and new technology subjects – became departments of Chemistry, Physics, Natural Science and a Scientific Laboratory. In 1868, the weather observatory of Tusculum was set up here thanks to the founder of astrophysics, professor Angelo Secchi.

In 1981, the University of Tor Vergata of Rome purchased Villa Mondragone.

The decorations of the Retirata, the two chapels, the Sala delle Cariatidi and Sala Rossa are still visible inside today.