The church is believed to have originated in the 3rd or 4th century as a meeting-place for the first Christians of Rome and an institution for aiding the poor, in the home of the lady Cyriaca. The name is thought to reflect its origins, as 'domnica' is probably a corruption of 'dominicum', a common Latin word for 'church', and especially for house-churches. It was built on the site of a Roman barracks. Her family's cemetery was where the basilica San Lorenzo fuori le Mura stands, and it was Cyriaca who arranged the burial of St Lawrence, deacon and martyr. St Lawrence used to hand out alms to the poor here.
The present church is from the time of Pope Paschal I, who had it rebuilt 818...822. Many of the older elements were preserved, but side apses were added in the Eastern style.
Alterations were made by the titular priest of the church, Giovanni Cardinal de'Medici, who later became Pope Leo X (1513-1521), with Andrea Sansovino as architect.
Church is also known as Santa Maria della Navicella after the small marble boat (navicella) in the piazza. The boat is a 16th century copy of an ancient one. The copy was placed here by сardinal de'Medici.
At the present time, the titular priest of the church is H.E. Luigi cardinal Poggi.
On the triumphal arch is an image of Christ between two angels and the apostles, and below the Moses and Elijah.
High up on the wall is a painted frieze in the Renaissance style made by Pierino del Vaga to a design by Giulio Romano, a student of Raphael.