The church is first mentioned in the Life of Pope Vigilius (537-553). In this text, Vilisarius patricius, the Byzantine general Belisarius, is attributed with the foundation of a xenodochium near Via Lata. The complex must also have included an oratory in which the origins of S. Maria in Trivio can be recognised. The church retains from its medieval phase only an inscribed lintel: originally placed above the central portal and today positioned out of context in a side wall of the building. The inscription explicitly mentions the patricius Belisarius referring, probably, to an episode in the Liber Pontificalis in which the general is made an accomplice of the emperor Justinian for the fraudulent deposition of Pope Silverius (536-537), who was replaced by Pope Vigilius (537-555). The text of the inscription implicitly condemns the undue interference of an emperor in the election of a pope, exhorting industrious repentance. The placement of this inscription above an entrance may therefore suggest, rather than a desire to celebrate the antiquity and prestige of the church, a clear anti-imperial stance. The appearance of the building today was given to it by Giacomo del Duca following work completed in 1575.

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