The analysis of new and published Hf and Nd isotopic data of late Cenozoic Andean arc igneous rocks from central Chile, coupled with our improved knowledge of orogenic processes in the region, reveals a tight link between major magmatic isotopic shifts and different Andean basement domains and timing of the main uplifting event. Oligocene–Miocene magmas from the Western Principal Cordillera show a nearly constant and juvenile composition (εHfI: +5 to +10; εNdI: +2 to +7), while those from the Eastern Principal Cordillera, formed since early late Miocene, are variably more enriched (εHfI: –4 to +4; εNdI: 0 to +3). Post–4.8 Ma magmas from both belts share an enriched signature (εNdI: –2 to +2) reflecting source contamination from east to west, contrary to the eastward subduction direction, in a process that occurred toward the end of the main Andean uplifting event. This results from the deep western basement underthrusting the orogen, and thus accounts for the westward propagation of the eastern enriched isotopic signatures approximately coeval with thickening and uplifting events. The observed patterns highlight the strong control exerted by the continental lithosphere on the composition of arc magmas over deep controls from the subduction-modified asthenospheric mantle. Moreover, they dynamically represent both (1) the hybridization affecting magmas ascending from the mantle in a heterogeneous continental lithosphere, and (2) the evolution of such lithosphere resulting from the thermal weakening and mass transfer processes occurring underneath cordilleran arcs during mountain building.