In the 1518, then the Cardinal Giulio de' Medici, cousin of the reigning pontiff Leo X, commissioned the initial design of the villa from Raphael.

In 1523, with Giulio de' Medici's ascension to Pope Clement VII, work restarted and the apartment and garden loggia were completed that year.

The decorations of the Villa are by Giulio Romano and Baldassare Peruzzi, both major architects in their own right; Giovanni da Udine completed the bas-reliefs in stucco, inspired by the classic Ancient Roman reliefs unearthed from the then rediscovered Domus Aurea of Nero; and finally, both Giovan Francesco Penni ("il Fattore") and the Florentine sculptor Baccio Bandinelli worked there too.

Aside from the Raphael loggia, the villa's greatest artistic element is the salone painted by Giulio Romano, with its magnificent vaulted ceiling.

The villa was restored by Count Carlo Dentice di Frasso, who acquired the property in 1925, and his American wife, the former Dorothy Cadwell Taylor.