Interactions between subduction dynamics and magma genesis have been intensely investigated, resulting in several conceptual models derived from geological, geochemical and geophysical data. To provide physico-chemical constraints on these conceptual models, self-consistent numerical simulations containing testable thermo-mechanical parameters are required, especially considering the three-dimensional (3D) natural complexity of subduction systems. Here, we use a 3D high-resolution petrological and thermo-mechanical numerical model to quantify the relative contribution of oceanic and continental subduction/collision, slab roll-back and tearing to magma genesis and transport processes. Our modeling results suggest that the space and time distribution and composition of magmas in the overriding plate is controlled by the 3D slab dynamics and related asthenospheric flow. Moreover, the decrease of the bulk lithospheric strength induced by mantle- and crust-derived magmas promotes the propagation of strike-slip and extensional fault zones through the overriding crust as response to slab roll-back and continental collision. Reduction of the lithosphere/asthenosphere rheological contrast by lithospheric weakening also favors the transmission of velocities from the flowing mantle to the crust. Similarities between our modeling results and the late Cenozoic tectonic and magmatic evolution across the eastern Mediterranean region suggest an efficient control of mantle flow on the magmatic activity in this region, which in turn promotes lithospheric deformation by mantle drag via melt-induced weakening effects.