The Messinian Salinity Crisis (5.85–5.35 Ma) represents a nearly unprecedented unloading and loading event. During the Messinian Salinity Crisis, two important things happened in terms of surface load changes—the accumulation of thick evaporites represent a load addition, while the desiccation of the Mediterranean represents a load subtraction. The desiccation and evaporite deposition were followed by the rapid addition of water, refilling the Mediterranean during the Zanclean. The calculated flexural response to load changes imposed significant changes on the horizontal stresses in the upper crust of the Northern Apennines, an active orogenic system characterized by simultaneous zones of extension and compression that migrated eastward over time. We show that these flexural stresses (approaching ± 50 MPa), added to the preexisting stresses across the Northern Apennines, were large enough to have caused some areas in compressional stress regimes to flip to extensional regimes, and vice versa. Among other things, our model predicts that the Marches Apennines region, which was beginning to undergo compression at the leading edge of the orogen, should have experienced a brief interval of extensional deformation. Previous structural studies of this region have shown that there was, in fact, a brief period of extensional faulting near the onset of the Messinian Salinity Crisis, which was then followed by a return to compressional deformation, just as our model predicts. The hypothesis presented here provides a novel explanation for this extension occurring in an area that should have been undergoing compression, one in which the unique events of the Messinian Salinity Crisis generated significant flexural stresses that changed the deformational regime during the relatively brief time of the Messinian Salinity Crisis. We further suggest that this hypothesis may provide insight into similar unexpected tectonic episodes during this time period in other parts of the Apennines.