The history of Castel Sant'Angelo begins in 135 AD, when Emperor Hadrian erected a funerary mausoleum for himself and his family in an outlying area of ​​ancient Rome. Also known as the Mole Adriana, it was built across the Tiber and connected to the city with the construction of the Pons Aelius, named after Emperor Aelius Hadrian, now known as the Ponte Sant'Angelo.

It served its original function as a tomb until around 403 AD, when it was included in the Aurelian Walls at the behest of Emperor Honorius and became an advanced bulwark beyond the Tiber to protect the city, taking on the new role of castellum. The imposing cylindrical mass housed the burial chamber containing the ashes of Roman emperors: from Hadrian to Antoninus Pius, from Septimius Severus to Caracalla, the last emperor whose deposition is documented.

In the early Middle Ages, the name Sancti Angeli was added, stemming from the legend that, in 590, Pope Gregory the Great had a vision of the Archangel Michael sheathing his sword atop Hadrian's Mole, symbolizing the end of the plague that was plaguing the city. In thanks, the pope built a church dedicated to Saint Michael, and a statue depicting the angel sheathing his sword was later placed there.

At the beginning of the 6th century, the castle was used as a prison by Emperor Theodoric. Subsequently, possession of the fortress was contested by numerous Roman noble families, until, in 1365, it was ceded by the Orsini family to the Church. Its proximity to St. Peter's and its solid, fortified structure tied its fortunes to those of the Church: the popes began using Castel Sant'Angelo as a refuge and as the home of the Vatican Archives. The castle underwent numerous renovations aimed both at strengthening its defensive structure and making it an increasingly magnificent papal residence.

Pope Nicholas III built the famous Passetto, which served as the pontiff's protected passage from St. Peter's Basilica to the fortress. Pope Alexander VI Borgia transformed it into a true military stronghold, building four pentagonal bastions and digging a moat. The same pope endowed the castle with a new apartment, frescoed by Pinturicchio, and added gardens and fountains.

The other popes who stayed within the fortress's walls undertook renovations and transformed it into a true papal residence, which reached its peak under Paul III. Pope Julius II built the Loggia overlooking the Tiber, which still bears his name today, created by covering up a section of the walkway that crowned the top of the fort's circular mass. The "stufetta," a small bathroom for taking medicinal baths, is associated with Pope Alexander VI. Its wall decoration was entrusted to Pietro Busdrago.

Paul III entrusted the renovation to the architects Raffaello Sinibaldi da Montelupo and Antonio da Sangallo the Younger, while the decoration of the rooms was entrusted to Perino del Vaga, whose grotesque fresco cycle can be found in the splendid Hall of Apollo: ten panels with a white background depicting the stories of Apollo.

Between 1667 and 1669, Pope Clement IX had ten marble angels placed on the Pons Aelius, since then also called the Ponte Sant'Angelo. The angel figures were designed by Gian Lorenzo Bernini and created by students from his workshop. The first two were sculpted by Bernini himself and are now preserved in the Church of Sant'Andrea delle Fratte.

After the unification of Italy, the castle was initially used as a barracks and political prison. In 1925, it became a national museum.