As the archetype of mountain building in subduction zones, the Central Andes has constituted an excellent example for investigating mountain-building processes for decades, but the mechanism by which orogenic growth occurs remains debated. In this study we investigate the Southern Central Andes, between 22° and 35°S, by examining the along-strike variations in Cenozoic uplift history (<45 Ma) and the amount of tectonic shortening-thickening, allowing us to construct seven continental-scale cross-sections that are constrained by a new thermomechanical model. Our goal is to reconcile the kinematic model explaining crustal shortening-thickening and deformation with the geological constraints of this subduction-related orogen. To achieve this goal a representation of the thermomechanical structure of the orogen is constructed, and the results are applied to constrain the main decollement active for the last 15 Myr. Afterwards, the structural evolution of each transect is kinematically reconstructed through forward modeling, and the proposed deformation evolution is analyzed from a geodynamic perspective through the development of a numerical 2D geodynamic model of upper-plate lithospheric shortening. In this model, low-strength zones at upper-mid crustal levels are proposed to act both as large decollements that are sequentially activated toward the foreland and as regions that concentrate most of the orogenic deformation. As the orogen evolves, crustal thickening and heating lead to the vanishing of the sharp contrast between low- and high-strength layers. Therefore, a new decollement develops towards the foreland, concentrating crustal shortening, uplift and exhumation and, in most cases, focusing shallow crustal seismicity. The north-south decrease in shortening, from 325 km at 22°S to 46 km at 35°S, and the cumulated orogenic crustal thicknesses and width are both explained by transitional stages of crustal thickening: from pre-wedge, to wedge, to paired-wedge and, finally, to plateau stages.