S. Giorgo falls within the territory of the parish of Santa Maria in Portico in Campitelli and is a rectory entrusted to the Canons Regular of the Order of the Holy Cross as well as a titular church, whose cardinal-deacons over the years have included Pope Boniface IX and Pope Martin V, as well as Pierre de Luxembourg (pseudocardinal of the Antipope Clement VII) and Saint John Henry Newman.

An inscription, dated in 461 or 482, found in the catacombs of St. Callixtus, probably refers of a church in the same zone, "LOCVS AVGVSTI LECTORIS DE BELABRV", though there is nothing to connect the lector with S.

The church was inside the Greek quarter of Rome, where Greek-speaking merchants, civil and military officers and monks of the Byzantine Empire lived — the nearby Santa Maria in Cosmedin, for example, was known as in Schola Graeca at the time.

The current church was built during the 7th century, possibly by Pope Leo II (682–683), who dedicated it to Saint Sebastian, who was martyred in this area and his corpse was thrown into the Cloaca Maxima.

[5] Pope Zachary (741–752), who was of Greek origin, moved the relic of St. George to here from Cappadocia, so that this saint had a church dedicated in the West well before the spreading of his worship with the return of the Crusaders from the East.

During this process, fragments (now displayed on the internal walls) were found, which indicated that a schola cantorum had existed on the site, which could be attributed to the period of Pope Gregory IV.