We investigated the recent evolution of the Po Plain–Alps system by integrating subsurface geophysical data from the Po Plain with new stratigraphic and structural observations from the Southern Alps margin. Inversion of structural data and chronology provided by stratigraphic constraints led to the definition of three tectonic events since the Pliocene, namely, the intra-Zanclean, the Gelasian, and the Middle Pleistocene, driven by an axis of maximum compression formerly oriented NE (intra-Zanclean) and then to the NNW (Gelasian and Middle Pleistocene). The associated deformation has been accommodated by two sets of faults consisting of NNE-trending thrust faults, mostly represented in the western sector of Lake Garda, and NW-trending strike-slip faults, observed in the southern and eastern sectors. The interplay between these two sets of faults is interpreted to produce short (<10 km length) thrust ramps activated in left transpression, bounded by longer (30–60 km) transfer faults activated in a right-lateral strike-slip motion. Based on this structural model, we infer moderate seismicity (Mw < 6) associated with the NNE-directed thrusts and stronger earthquakes (also Mw > 6.5) along the NW-trending strike-slip faults. In this framework, the newly defined Nogara fault and the Sant’Ambrogio fault, all pertaining to the NW-trending system, are regarded as potential candidates for the seismogenic source of the January A.D. 1117 event, the most destructive earthquake in the Po Plain.