The Salento Peninsula (Apulia, southern Italy), along with a few other regions in Italy, is traditionally considered a low seismic hazard area. However, in 1743 it was affected by the catastrophic effects (Imax=IX-X MCS) of an earthquake, that probably occurred offshore, in the Salento Plateau (Ionian Sea). Subsequent damage had a complex pattern, whereby some towns were almost razed to the ground and others, nearby, suffered only slight damage. By means of an integrated geological, geotechnical and geophysical analysis we tried to cast a light on the causes of this peculiar distribution of seismic shaking, which we finally modelled by means of a one-dimensional simulation. These results, together with the re-analysis of the macroseismic distribution of the earthquake, and the seismotectonic knowledge of the region, suggest that the 1743 event was a strong, deep one that occurred far from Salento. The event induced high amplification, mainly in the villages (i.e., Nardò and Francavilla Fontana) founded on thin Pleistocene basins filled with soft sediments. The highest amplification peak, due to both the spectral content of the earthquake, as well as to the resonant period of the sedimentary basins, occurred in the same frequency range as most of the buildings of the time, that is ~3 Hz. This terrific double-resonance effect seems to be the main cause for the highest intensity evaluated in Salento, which, would otherwise, have been struck by effects possibly close to VII-VIII MCS.