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In 1781, Stanislaus Poniatowski, nephew of the last king of Poland, bought the villa, which had belonged to Cardinal Pier Donato Cesi in the first half of the 16th century, from Marquis Giulio Sinibaldi.

In the early 19th century, the Polish prince commissioned Giuseppe Valadier to transform the 16th-century building near Villa Giulia in Via dell'Arco Oscuro into a villa. Depicted in engravings by Venturini (1683) and Vasi (1757), the building was already mentioned in 1581 by Montaigne as Villa Cesi.

After Valadier's intervention, the main entrance to the villa faced Via Flaminia, rising on a terrace accessed by a cordonade, which still exists today, flanked by basins and fountains fed by a branch of the Acquedotto Vergine. The large garden, formed by terraced terraces and adorned with ancient sculptures, was closed at the top, towards the mountain, by a pergola known as the "loggia of delights". The decorations in the villa's reception rooms are particularly refined and have been restored to their original appearance, such as the Sala dell'Ercole Farnese on the ground floor or the Sala delle Colonne Doriche on the first floor.

Various events have gradually modified the villa and the park; damaged during the clashes between Garibaldi and the French in 1849, the complex was transformed in the years following the unification of Italy by the new owner Riganti, who built a two-storey tannery in the garden area. 
Villa Poniatowski was purchased by the State in 1989 after a long process of expropriation to accommodate the expansion of the nearby National Etruscan Museum of Villa Giulia and thus create the "Etruscan Museum Centre of Rome". 

From 1997 to 2010, the complex underwent systematic architectural restoration work and work to adapt the spaces for use as a museum. The collection on display is really rich. It includes funerary objects from the necropolis of Terni, Nocera Umbra, Gualdo Tadino and Todi, as well as a rich collection of objects from the princely tombs found in the necropolis of Colombella. There is also material from the Latium vetus, the Tomba "degli ori" from the Peschiera necropolis and finally, on the main floor of the villa, the sanctuary dedicated to Mater Matuta from Satrico, the ex-votos found in the extra-urban temple of Alatri and the gifts to the divinities from the temple of Juno Moneta on the acropolis of Segni.

The 'long sleeve' above the Riganti Tanneries houses the Institute's Library, now enriched by the Maria Santangelo and Mario Moretti funds and by the rich library that formerly belonged to Massimo Pallottino and was deposited at the Soprintendenza by the CNR's Institute of Italic Sciences and the Ancient Mediterranean.

Important discoveries were made in the course of the work, including the early 16th-century layout of the Villa with the remains of the two fountains located on the western façade, the numerous basins and fountains that adorned Valadier's Italian garden and the pictorial and decorative cycles in the Hercules Room, the Indian Room and the Egyptian Room with its perspective colonnade.