The basilica of Santa Maria in Cosmedin is in an area of Rome along the Tiber River that once housed the Forum Boarium, the ancient cattle market, and a complex of temples and shrines to Hercules.

Archaeologists discovered a platform of ancient tufa under the crypt of the church, which they have tentatively identified as part of the Great Altar of Unconquered Hercules (Latin: Herculis Invicti Ara Maxima), possibly dating from the sixth century BCE.

Several waves of eastern refugees added to the population as they fled from wars and persecution, the encroachment of Islam, and the violence of the Iconoclastic Controversy in the Christian East.

[6] The brick masonry of the building was not typical of Rome at this time but was common in Naples in the sixth century, suggesting the work was done by Greek or South Italian builders, perhaps immigrants residing in the schola graeca.

A mid-eighth century inscription displayed in the narthex records a gift of extensive properties to the church's ministry to the poor by Eustathius (or Eustachius), a Byzantine duke of Rome who had administered the territory of Ravenna for the papacy.

[14] On the upper level of the outer walls, rows of clerestory windows repeated the motif of the arches in the diaconia that had opened into galleries.

[15] By the ninth century, the church was known as Santa Maria in Cosmedin, probably the Latinization of κοσμίδιον (kosmidion), derived from the Greek word κόσμος, meaning "ornament, decoration.

"[16] At the same time, Pope Hadrian had a crypt dug from the volcanic tufa slab under the east end of the church, possibly the podium of the Great Altar to Hercules.

A number of inscriptions state that the renovations were paid for by Alfanus, a wealthy layman or cleric who served as papal chamberlain (Latin: camerarius) to Callixtus.

The center door is created of marble elements from older Roman buildings, with medieval carvings signed by a "Giovanni of Venice" (IOHANNIS DE VENETIA ME FECIT).

[28] The nave floor in the renovated church was a creation of the Cosmati family, Roman architects, sculptors, and decorators, who specialized in pavements formed of slabs of marble and semi-precious stones set in gold and colored mosaics, called opus Alexandrinum.

Santa Maria in Cosmedin is thought to have a particularly beautiful floor with a large central disc of porphyry, a costly purple stone highly prized by Roman emperors.

Only the uppermost row between the clerestory windows survives intact and depicts scenes from the lives of the prophets Daniel and Ezekiel, warning against the evils of idolatry; the subjects are very unusual in medieval art.

[35] Pope Eugenius IV (papacy 1431–47) gave Santa Maria in Cosmedin in 1435 to the Benedictine community of San Paolo; after the monks' departure in 1513, the church began to fall into disrepair.

[36] In 1718, Cardinal Annibale Albani commissioned a new stucco facade and other refurbishments designed in the late Baroque style of the time by Giuseppe Sardi.