The Altemps Palace was built in 1477 by Girolamo Riario, Duke of Imola and nephew of Pope Sixtus IV (1471-1484), on previous Medieval buildings, including small terrace houses, towers and gardens probably making up a single fortified complex defending this section of the Tiber embankment. 

This building phase saw the participation of Melozzo da Forlì, Luca Pacioli and perhaps Leon Battista Alberti. In 1511 the building was sold to cardinal Francesco Soderini. Other restructuring work was carried out during the 16th century, above all, after 1524, when cardinal Soderini died, and the palace became the home of cardinal Innocenzo Cybo. Baldassarre Peruzzi is thought to have worked on the building in this period. 

In 1568 the palace was bought by cardinal Marco Sittico Altemps, the son of the German count Wolfgang Hohenems (known as Altemps in Italy) and of Chiara Medici, sister of Pope Pius IV (1560-1565). Cardinal Marco Sittico made considerable changes to the building between 1577 and 1595, the year of his death. This work was planned by Martino Longhi the Elder and he was responsible for, amongst other things, the roof-terrace created in the corner towards Piazza S. Apollinare; this terrace was surmounted by four pyramid-shaped spires and covered by a dome topped with a rampant ram – the symbol of the Altemps family. 

Many great artists took part in the works, including Giacomo Della Porta, Flaminio Ponzio, Tommaso Schiratti, Girolamo Rainaldi and Onorio Longhi. At the start of the 17th century, Duke Giovanni Angelo Altemps, the nephew of cardinal Marco, built the chapel of S. Aniceto, the Goldoni theatre, considered to be one of the oldest theatres in Rome, and the library. The chapel housed the relics of the martyr Pope Aniceto (155-166 AD) that were found in the catacombs of Saint Calistus and granted by Pope Clement VIII in 1603; this is the only case of a pope buried in a private building. The chapel was decorated by Pomarancio and by Ottavio Leoni. 

In 1887 the palace became the property of the Holy See and became the seat of the Pontifical Spanish College. In 1982 it was purchased by the Italian State and, after a long restoration work, became the seat of the National Roman Museum, housing what remained of the Altemps collection and other important collections of ancient works, such as the Boncompagni Ludovisi collection, the Mattei collection and the Del Drago Albani collection. 

The palace has an L-shaped plan and is of three storeys: the first floor has simple corniced windows, the second has architraved windows with balconies and the third has architraved windows. The building is crowned with a cornice and trusses. 

The face overlooking Piazza S. Apollinare has many mews entrances, while the face overlooking Via di S. Apollinare has the main entrance and ashlar cantonal structures. This entrance leads on to the courtyard with arcades opening on the entrance side and on the opposite end, closed with windows on the other two sides, and decorated with the Altemps and Orsini crests. Some of the statues making up the great Altemps collection are found here.