The 9th September, 1349, earthquake was one of the most catastrophic events experienced along the Apennines. At least three main shocks struck a vast area of the Molise–Latium–Abruzzi regions, and damage was even sustained by the distant monumental buildings of Rome. The southern-most shock (Mw ~ 6.7) occurred at the border between southern Latium and western Molise, razing to the ground the towns of Isernia, Venafro and Cassino, amongst others, and devastating Montecassino Abbey. As with other Medieval catastrophic sequences (e.g., in December 1456, Mw ~ 6.5–7.0), this earthquake has not yet been associated to any seismogenic source; thus, it still represents a thorn in the flesh of earthquake geologists. We have here carried out a reappraisal of the effects of this earthquake, and through an interpretation of aerial photographs and a field survey, we have carried out paleoseismological analyses across a poorly known, ~N130 normal fault that crosses the Molise–Campania border. This structure showed repeated surface ruptures during the late Holocene, the last one of which fits excellently with the 1349 event, both in terms of the dating and the rupture dimension. On the other hand, archaeoseismic analyses have also indicated the faulting of an Augustean aqueduct. The amount of apparent offset of the aqueduct across the fault traces shows that there were other surface faulting event(s) during the Roman–High Middle-Age period. Therefore, in trying to ascertain whether these events were associated with known (potentially of 346 AD or 848 AD), or unknown earthquakes in the area, it became possible that this ~20-km-long fault (here named the Aquae Iuliae fault) is characterized by high slip rates and a short recurrence time. This is in agreement with both the similar behaviour of the neighbouring northern Matese fault system, and with recent GPS analyses showing unexpectedly high extension rates in this area.