The non-collisional subduction margin of South America is characterized by different geometries of the subduction zone and upper-plate tectono-magmatic provinces. The localization of deformation in the southern Central Andes (29°S–39°S) has been attributed to numerous factors that combine the properties of the subducting oceanic Nazca plate and the continental South American plate. In this study, the present-day configuration of the subducting oceanic plate and the continental upper plate were integrated in a data-driven geodynamic workflow to assess their role in determining strain localization within the upper plate of the flat slab and its southward transition to a steeper segment. The model predicts two fundamental processes that drive deformation in the Andean orogen and its foreland: eastward propagation of deformation in the flat-slab segment by a combined bulldozing mechanism and pure-shear shortening that affects the broken foreland and simple-shear shortening in the fold-and-thrust belt of the orogen above the steep slab segment. The transition between the steep and subhorizontal subduction segments is characterized by a 370-km-wide area of diffuse shear, where deformation transitions from pure to simple shear, resembling the transition from thick to thin-skinned foreland deformation in the southern Sierras Pampeanas. This pattern is controlled by the change in dip geometry of the Nazca plate and the presence of mechanically weak sedimentary basins and inherited faults.