The catacomb is especially renown for the most famous martyr buried in it, Pancras from Phrygia, who came to Rome together with his uncle Dionysus after his parents' death and was decapitated in 304 after refusing to sacrifice to the gods. His body was abandoned on the Via Aurelia and was picked up by a Christian matrona, Ottavilla, who buried him in the closest graveyard, that she probably owned. The cult of St. Pancras highly spread during the Middle Ages, so much so that the catacomb bearing his name was one of the few in Rome that could always be visited by the pilgrims. The first notice about the martyrdom of Pancras comes from the Martyrologium Hieronymianum, that sets the date of the death at 12 May.
The ancient sources, particularly the Medieval itineraries for pilgrims, mention other martyrs buried within the catacomb: Artemy, Paulinus, Sophia and her three daughters Faith, Hope and Charity. The resting place of the last four martyrs can probably be identified with the so-called cubicle of St. Sophia.
Between the end of the 4th century and the beginning of the 5th, Pope Symmachus built above the catacomb a basilica consecrated to the martyr and a thermal edifice. In 594 Gregory the Great provided the basilica with a cloister. In 625 Pope Honorius I rebuilt the basilica, with three naves.
As mentioned above, San Pancrazio is one of the few catacombs in Rome whose track has not been completely lost during the centuries, even if it has often been confused with other catacombs rising along the Via Aurelia. Antonio Bosio thoroughly studied the cemetery, but he confused it with the cemetery of Calepodius; the two catacombs were distinguished by Giovanni Battista de Rossi in the 19th century.
Excavations carried out at the beginning of the 1930s under the floor of the Basilica of San Pancrazio led to the discovery of a Roman street that cut in two diagonally the church; they also brought to light some mausolea and ground graves, both inside the basilica and in its square, such demonstrating that the hypogeous cemetery also included an extended funerary area on the topsoil.