[1] The inscription on the episcopal throne states that this is the first church in Rome dedicated to Mary, mother of Jesus, although some claim that privilege belongs to the Basilica di Santa Maria Maggiore.

Although nothing remains to establish with certainty where any of the public Christian edifices of Rome before the time of Constantine the Great were situated, the basilica on this site was known as Titulus Callisti, based on a legend in the Liber Pontificalis, which ascribed the earliest church here to a foundation by Pope Callixtus I (died 222), whose remains, translated to the new structure, are preserved under the altar.

The inscriptions found in Santa Maria in Trastevere, a valuable resource illustrating the history of the Basilica, were collected and published by Vincenzo Forcella.

The 22 granite columns with Ionic and Corinthian capitals that separate the nave from the aisles came from the ruins of the Baths of Caracalla, as did the lintel of the entrance door.

The "Coronation of the Virgin" (1130–1143) sits atop an apse vault, and depicts Pope Innocent II holding a model of the church.

In the Capella Altemps there is a unique icon of the enthroned Virgin and Child "The Madonna della Clemenza", a panel painting in encaustic, dated between the 6th and 9th century CE, probably of the Byzantine origins.

In the dome, there is an opening or oculus from which four putti emerge to carry a central tempietto, all of which frames a light-filled chamber above, illuminated by windows not visible from below.

Later traditions give the names of the early patrons of the tituli and have retrospectively assigned them the title of cardinal.

[citation needed] Among past cardinal priests holding the honorary titulus of Santa Maria in Trastevere have been: The incumbent titular holder is Carlos Osoro Sierra, Archbishop Emeritis of Madrid.

On March 25, 1887, Cardinal James Gibbons took possession of this titular church and "delivered a powerful sermon defending the American constitutional model of church-state relations.

"[13] In July 2014, the wedding of Prince Amedeo of Belgium, Hereditary Archduke of Austria-Este, and Elisabetta Rosboch von Wolkenstein was held at the basilica.

[14] On March 11, 2018, Pope Francis celebrated mass at the basilica to commemorate the 50th anniversary of the foundation of the Community of Sant'Egidio.