The basilica was founded by Pope Sylvester I on a site donated by one Equitius (hence the name of Titulus Equitii) in the 4th century.

The current church of San Martino ai Monti dates from the Carolingian era, but remains of a 3rd-century pillared hall have been located below and adjacent to it.

Some scholars have identified this earlier building with the Titulus Equitii, but according to Hugo Brandenburg, it is "most unlikely that it could have served as a place of worship for any larger community and its liturgy: The original purpose of this fairly modest hall ... was probably to serve as a storage space for commercial purposes."

During the Investiture Controversy and the Gregorian Reforms, the priest of San Martino, Beno, supported the Antipope Clement III.

The inscriptions found in S. Martino ai Monti, a valuable source illustrating the history of the Basilica, have been collected and published by Vincenzo Forcella.

A votive lamp, made in silver sheet and housed in the sacristy, was believed to be St. Sylvester's tiara.

Under the major altar are preserved the relics of Saints Artemius, Paulina and Sisinnius, brought here from the Catacomb of Priscilla.

Galeazzo Leoncino painted a fresco of Pope Silvester holding the Council of 324 in the church of San Martino, Pietro Testa the Vision of St Angelo the Carmelite in the Wilderness, and Filippo Gherardi an altarpiece of San Carlo Borromeo.