The church had its beginning as a simple oratory added to a family villa suburbana of Pope Gregory I, who converted the villa into a monastery, ca 575-80, before his election as pope (590). The community was dedicated to the Apostle Andrew; it retained its original dedication in early medieval documents, then was recorded after 1000 as dedicated to Gregory the Great. Its name in Clivo Scauri records its site along the principal access road, the ancient Clivus Scauri that rose up the Caelian slopes from the valley between the Palatine Hill and the Caelian . The decayed church and the small monastery attached to it on the now-isolated hill passed to the Camaldolese brothers in 1573.The current edifice was rebuilt on the old site to designs by Giovanni Battista Soria in 1629-1633, commissioned by Scipione, Cardinal Borghese; work was suspended with his death, and taken up again in in 1642. Francesco Ferrari (1725-1734) designed the interior.
The church is preceded by a wide staircase rising from the via di San Gregorio, the street separating the Caelian hill from the Palatine. The façade, the most prominent and artistically successful work of Giovanni Battista Soria (1629-33), resembles in its style and material (travertine), that of San Luigi dei Francesi; it is not the façade of the church however, but instead leads into a forecourt or peristyle, at the rear of which the church itself can be reached through a portico (illustration, left) that contains some tombs: these once included that of the famous courtesan Imperia, lover of the rich banker Agostino Chigi (1511), but later it was adapted to serve as the tomb of a 17th-century clergyman. The marble cathedra associated with Gregory the Great is preserved in the stanza di S. Gregorio in the church; a shrewd and accurate reconstruction of its ancient appearance was illustrated as Gregory's throne by Raphael in the Disputà. The lion-griffin protomes that form its front and appear in Raphael's fresco are continued on the sides in an acanthus scroll. Three more marble thrones of precisely the same model may be seen in the Isabella Stewart Gardner Museum, Boston, in Berlin and in the Acropolis Museum; Gisela Richter suggested that all are replicas of a lost late Hellenistic original; none of the replicas has preserved the separately-carved base that would have continued the lions' legs, very much as Raphael surmised.
The church follows the typical basilican plan, a nave divided from two lateral aisles, in this case by sixteen antique columns with pilasters. Other antique columns have been reused: four support the portico on the left of the nave that leads into the former Benedictine burial ground, planted with ancient cypresses, and four more have been reused by Flaminio Ponzio (1607) to support the porch of the central oratory facing into the burial ground on the far side, which is still dedicated to Saint Andrew.
The grounds of the oratories also include some substructures of the Roman imperial period, that may merely have been tabernae, but one of which exhibits striking features that encourage some experts to think is an early Christian meeting place and baptismal pool.
In the grounds of the Camaldolese monastery of San Gregorio al Celio was discovered the Aphrodite of Menophantos, a Greco-Roman marble Venus of the Capitoline Venus type, now in the Museo Nazionale Romano. The Camaldolese coenobites occupied this ancient church and monastery of S. Gregorii in Clivo Scauri; the sculpture came into the possession of prince Chigi. Johann Joachim Winckelmann described this sculpture in his Geschichte der Kunst des Altertums
The villa possessed by the family of Gregory, who had already provided one pope (Felix III), seems to have had a distinguished early history. Gregory himself had the reputation among approving medieval writers following Martin of Opava's thirteenth-century Chronicle of Emperors and Popes of having been a dedicated smasher of idols; when such actions became instead a cause of sorrow and loss, beginning with Ghiberti and taken up by Renaissance humanists, in 1527 Andrea Fulvio was at pains to deny as a malicious rumor the old story that Gregory "had ordered all the most beautiful statues...should be thrown into the Tiber so that men, captivated by their beauty, should not be led astray from a religion that was still fresh and recent.