The site of the Catacomb of Saint Calixtus is 15 ha in area and almost 20 km in length.

One of the oldest and largest catacombs is that of St Calixtus on the Via Appia Antica. Named after the future pope, who as a deacon was charged with overseeing the Christian cemeteries in the time of Pope Zephyrinus (reigned 199-217), it included the graves of a number of 3rd-century popes (the crypt of the Popes, or Capella dei Papi). The majority of dated catacomb burials, however, belong to the 4th and 5th centuries. In the adjoining crypt is the grave of Saint Cecilia, whose relics were removed by Pope Paschal I in 821: the early 9th century frescoes on the walls represent Saint Cecilia praying. The crypt fell into disuse and decay as the remaining relics were translated from the catacombs to the various churches of Rome; the final wave of translations from the crypt occurred under Pope Sergius II in the 9th century before the Lombard invasion, primarily to San Silvestro in Capite, which unlike the Catacomb was within the Aurelian Walls. It was rediscovered in 1854 by the pioneering Italian archaeologist Giovanni Battista de Rossi.