We investigated the late Upper Pleistocene activity of the eight main faults that comprise the active, dip-slip Gran Sasso fault system (GSFS) in the Gran Sasso d'Italia Massif (central Italian Apennines; 2912 m a.s.l.). We carried out novel paleoseismological analyses at four sites of three different fault segments, and reviewed the data of the previous results for three other segments. We carried out several topographic profiles across the offset hillslopes, alluvial fans, glacial cirques, moraines, and valley floor. Through the dozen radiocarbon datings that were combined and cross-checked with many other ages published in previous studies, we have provided robust slip-rates and reconstructed the Holocene seismic history of this fault system. Paleoseismic analyses revealed the presence of three consecutive earthquakes since the onset of the Late Holocene, which were separated by 3.3 ky and 2.2 ky, respectively. The last one occurred in the 13th–14th century CE, a time-span that fits with the catastrophic 1349 seismic sequence. Our review of the macroseismic intensity distribution of this sequence indicates the existence of two distinct mesoseismic areas; a southern one that was already related to the Aquae Iuliae fault rupture (Abruzzi-Campania-Molise borders), and a northern one that robustly matches the hanging-wall of the Gran Sasso fault system. Given the length of this fault system, we estimated Mw 7 for its entire rupture, which accounts for the total destruction of L'Aquila and the neighboring villages. This also accounts for the strong effects and severe damage suffered by several settlements in the para-Tyrrhenian far field, especially to buildings characterized by long fundamental resonance periods, as seen for the monuments of Rome. Although characterized by long recurrence times (2.8 ± 0.5 ky), our results suggest that as for all of the main silent faults of the eastern set of active structures in the central Apennines, this fault system has one of the largest seismogenic potentials of the whole Apennine chain, with seismic risk implications extended even to its far-field.