Built at the beginning of the 20th century, at the crossing between Amalias Avenue and Dionysiou Areopagitou Street, as the residence of the Egyptiot lawyer Georgios Orphanidis and his wife Olga Saroglou, sister of the donor of the Saroglio Mansion, the building was designed by the Athenian architect Anastasios Metaxas (1862–1937). Metaxas was the architect in charge of the reconstruction plans for the Panathenaic Stadium in Athens, as well as the architect of numerous public and private buildings at the Greek capital. These include the French Embassy, Eginitio Hospital, Andreas Syggros Hospital, and the building that currently houses the Benaki Museum, among others. Despite a predominant eclecticism in the architectural style of the period, evident in the works of Ernst Ziller, Metaxas remained faithful to a more austere and rather simple neoclassicism; in the case of the Foundation’s building, its style is in complete harmony with the nearby archaeological monuments.

During the 1930s, it was the residence of the Kalligas family. From around 1937–38 to 1950, it became the Italian School of Archaeology, which also housed its then Director. The World Craft Council (WCC) was its last tenant; the building was used as an exhibition space during this time.

In 1989, the Onassis Foundation acquired the neoclassical building. The wear and tear of time and the reckless modifications dating back to the interwar period had altered both its façade and the interior spaces. In 1991, after an initial phase of architectural study, the architect Vassilis Tseghis completed the restoration of the building. In 2009, aiming to support, promote, and develop education and culture in Greece, the Onassis Foundation established the Onassis Library on the ground floor, designed by architect Konstantinos Sp. Staikos. In 2006, the building opened to the public for the first time, providing free admission to exhibitions, tours, and educational programs.