The main structure of the basilica and the monastic complex of the church was built over the library of the Forum of Peace (Bibliotheca Pacis) which also incorporated the adjacent fourth century CE Temple of Romulus.

The bodies of Saints Mark and Marcellian were translated, perhaps in the ninth century CE, to this church, where they were rediscovered in 1583 CE during the reign of Pope Gregory XIII.

circa 527 CE-

The temple was Christianised and dedicated to Santi Cosma et Damianus in 527, when Theodoric the Great, king of the Ostrogoths, and his daughter Amalasuntha donated the library of the Forum of Peace (Bibliotheca Pacis) and a portion of the Temple of Romulus to Pope Felix IV.

The pope united the two buildings to create a basilica-complex devoted to two Arabian Christian brothers and saints, Cosmas and Damian, in contrast with the ancient pagan cult of the two brothers Castor and Pollux, who had been worshipped in the nearby Temple of Castor and Pollux. The apse of the basilica was decorated with a Roman-Byzantine mosaic, representing a parousia, the Second Coming of Christ at the end of time.

In 1632, Pope Urban VIII ordered the restoration of the basilica. The works, projected by Orazio Torriani and directed by Luigi Arrigucci, raised the floor level seven metres, bringing it equal with the Campo Vaccino, thus avoiding the infiltration of water. Also, a cloister (inspect) was added. The old floor of the basilica is still visible in the lower church, which is the lower part of the first church.

In 1947 CE, the restorations of the Imperial Forums gave a new structure to the church. The old entrance, through the Temple of Romulus, was closed, and the temple was restored to its original forms; with the Pantheon, the Temple of Romulus is the best preserved pagan temple in Rome. A new entrance was opened on the north side (on via dei Fori Imperiali), whose arch gives access to the cloister, and through this to the side of the basilica.

circa 527 CE

Next to the new entrance to the complex from the Via dei Fori Imperiali, there are the rooms with the original marble paving of the Forum of Peace (Templum Pacis), also known as the Forum Vespasiani, and the wall where the 150 marble slabs of the Forma Urbis Romae were hung. Through the cloister, the entrance to the church opens on the side of the single nave. The plan of the basilica followed the norms of the Counter-Reformation: a single nave, with three chapels on each side, and the big apse, which now looks quite oversized because of the reduction in height of the 17th-century CE restoration, framed by the triumphal arch, also mutilated by that restoration.

The mosaics are masterpieces of 6-7th century CE art. In the middle is Christ, with Saint Peter presenting Saint Cosmas and Saint Theodorus (right), and Saint Paul presenting Saint Damian and Pope Felix IV; the latter holds a model of the church.