The southern Central Andes (SCA) (between 27° S and 40° S) is bordered to the west by the convergent margin between the continental South American Plate and the oceanic Nazca Plate. The subduction angle along this margin is variable, as is the deformation of the upper plate. Between 33° S and 35° S, the subduction angle of the Nazca plate increases from sub-horizontal (< 5°) in the north to relatively steep (~ 30°) in the south. The SCA contain inherited lithological and structural heterogeneities within the crust that have been reactivated and overprinted since the onset of subduction and associated Cenozoic deformation within the Andean orogen. The distribution of the deformation within the SCA has often been attributed to the variations in the subduction angle and the reactivation of these inherited heterogeneities. However, the possible influence that the thickness and composition of the continental crust have had on both short-term and long-term deformation of the SCA is yet to be thoroughly investigated. For our investigations, we have derived density distributions and thicknesses for various layers that make up the lithosphere and evaluated their relationships with tectonic events that occurred over the history of the Andean orogeny and, in particular, investigated the short- and long-term nature of the present-day deformation processes. We established a 3D model of lithosphere beneath the orogen and its foreland (29° S–39° S) that is consistent with currently available geological and geophysical data, including the gravity data. The modelled crustal configuration and density distribution reveal spatial relationships with different tectonic domains: the crystalline crust in the orogen (the magmatic arc and the main orogenic wedge) is thicker (~ 55 km) and less dense (~ 2900 kg/m3) than in the forearc (~ 35 km, ~ 2975 kg/m3) and foreland (~ 30 km, ~ 3000 kg/m3). Crustal thickening in the orogen probably occurred as a result of stacking of low-density domains, while density and thickness variations beneath the forearc and foreland most likely reflect differences in the tectonic evolution of each area following crustal accretion. No clear spatial relationship exists between the density distribution within the lithosphere and previously proposed boundaries of crustal terranes accreted during the early Paleozoic. Areas with ongoing deformation show a spatial correlation with those areas that have the highest topographic gradients and where there are abrupt changes in the average crustal-density contrast. This suggests that the short-term deformation within the interior of the Andean orogen and its foreland is fundamentally influenced by the crustal composition and the relative thickness of different crustal layers. A thicker, denser, and potentially stronger lithosphere beneath the northern part of the SCA foreland is interpreted to have favoured a strong coupling between the Nazca and South American plates, facilitating the development of a sub-horizontal slab.