The first church on this site was built in 939, when Odo of Cluny was given the Roman palace of Alberic II of Spoleto, which was then converted into a Cluniac Benedictine monastery.[1] The young Hildebrand studied and took his first monastic vows here.[2] When the monastery was dissolved in the 14th century, the site was acquired by the Knights of Malta, who had the church rebuilt in the 1550s.

In 1760, the papal nephew and Grand Prior of the Knights, Cardinal Giovanni Battista Rezzonico, sought to improve the appearance of the buildings. On a limited budget, the church was substantially renovated between 1764-66 according to the designs of Giovanni Battista Piranesi. It is his only architectural work. According to a 2019 account, he "consolidated the structure of the 16th-century church and raised the side walls...restored the vault and designed the decoration for its new aspect".[3] Piranesi also designed the piazza in front of the church, the Piazza dei Cavaliere di Malta. The fairly low wall around the piazza is articulated by panels with paired obelisks with stelae positioned between them.

The Neo-Classical facade has paired fluted pilasters towards its edges to infer a temple front. The vertical linearity of the fluted pilasters act as a foil to enhance the more decorative reliefs of the facade. The reliefs on this facade, the entrance gate and the panels and stellae in the piazza include emblems and other references to the military and naval associations of the Knights of Malta and the Rezzonico family heraldry. The way in which they are represented indicates Piranesi's fascination with Rome's ancient past as they allude to motifs from Ancient Rome and Etruria.[4]

The keyhole of the Priory, at 3 Piazza dei Cavalieri di Malta, is famous. Looking through it, one can see a fantastic panorama of the dome of St. Peter perfectly framed by the hedges of the Priorato gardens. The keyhole was deliberately placed here, as part of Piranesi's design.[5]