Cenozoic contractional deformation in the North-Iberian continental margin (southern Bay of Biscay) led to the uplift of the Cantabrian Mountains and the northward subduction of part of the thick continental crust, down to at least ~ 55 km depth beneath the coastline, and perhaps even ~ 30-40 km deeper. In order to provide a more constrained model of this unique structure and gain insight into the factors controlling its evolution, we performed an integrated geophysical-petrological modeling of the lithosphere along a 470 km-long, N-S transect down to 400 km depth. The methodology used allows for fitting gravity anomalies, geoid undulations, surface heat flow, elevation and seismic velocities with a realistic distribution of densities and seismic velocities in the mantle and the subducting lower crust, which are dependent on chemical composition, pressure and temperature. Two models are presented, with variable maximum depth for the crustal root: 60 km (Model A) and 90 km (Model B). Results indicate that both models are feasible from the geophysical point of view, but the shallower root agrees slightly better with tomographic results. The thickness of the thermal lithosphere in Model A varies from 125-145 km south of the Cantabrian Mountains, to 170 km beneath the crustal root and 135-140 km beneath the central part of the Bay of Biscay. Model B requires a thicker thermal lithosphere beneath the crustal root (205 km). Low seismic velocities beneath the Bay of Biscay Moho and in the mantle wedge above the crustal root are explained by the addition of 1-2 wt% of water. Input from dehydration reactions in the subducting lower crust is ruled out in Model A and has a very minor influence in Model B. We therefore interpret the water to have percolated from the seafloor during the formation of the margin in the Mesozoic. A later basaltic underplating was also inferred. A tentative evolutionary model governed to a great extent by these petrological processes is proposed, implying a minimum shortening close to 100 km from the Latest Cretaceous to the present.