This cemetery, named after the martyr St. Sebastian, who is buried here, was originally called "ad catacumbas". According to the widely acknowledged explanation, the name signifies "near the hollows", because of the mines of tuff located in this area. The name was later used generally to indicate all subterranean Christian cemeteries.

Another ancient name of the cemetery was "Apostolic Memorial" (Memoria Apostolorum). The name derives from the liturgical celebrations, dedicated to the Apostles Peter and Paul, which took place here for a limited period in the first centuries.

From the first century, the site had been intensely exploited and constructed upon. The caves and the tunnels of the mines were used for pagan and Christian rectangular wall tombs (loculi), as well smaller tombs (colombari) used to house urns. At least two residential buildings were constructed above ground, especially noted for their interior wall painting decorations.

Around the middle of the second century, a cave-in occurred, and in the square which was constructed above ground, three mausoleums were built, respectively belonging to Clodius Hermes, the Innocentores and "sub Ascia". Later this area was again covered over and a portico enclosed by a wall (triclia) was built. Along the wall, hundreds of graffiti writings, dedicated to Peter and Paul, have been deciphered. Around the year 258, the religious celebrations commemorating the two Apostles were transferred to the site, and the emperor Constantine (306-337) had a grandisose circiform basilica constructed in the honour of the Apostles. Meanwhile, the catacomb had been developing underground from the third century. As it is well known from archeological and literary sources, the martyrs Sebastian and Eutychius were buried here..