Many studies propose a significant shift in the tectonic and paleogeographic evolution of the Andes in south-central Chile and Argentina during the Late Cretaceous. It has been proposed that the preceding Jurassic-Early Cretaceous extensional regime that resulted in a low-relief volcanic arc and the backarc Neuquén basin came to an end, giving way to shortening and Andean growth from the Late Cretaceous onward. Nevertheless, there are disagreements regarding the timing and nature of this transition to Andean orogenesis. To address these issues, we conducted geochronologic (U–Pb and 40Ar/39Ar), sedimentologic, and structural studies on Mesozoic-Cenozoic sedimentary and volcanic rocks in the Río Maule area (Principal Cordillera, Chile, 36°S). From our findings and prior analyses, we propose the following tectono-stratigraphic evolution of the region. (1) Marine deposition of the Tithonian-Hauterivian Baños del Flaco Formation took place in an extensional backarc basin. (2) After a ∼ 40 Myr hiatus, fluvial deposits of the Colimapu Formation and volcanic rocks of the Plan de los Yeuques Formation accumulated during the Cenomanian-Danian. Whereas the Colimapu Formation displays evidence of syndepositional shortening, the Plan de los Yeuques Formation exhibits synextensional growth strata. Contrary to other studies, our results suggest that the Chilean part of the Principal Cordillera was largely a zone of active deposition rather than an elevated fold-thrust belt during the Late Cretaceous. We propose that sedimentation occurred within a series of relatively stable intermontane subbasins generated by shortening, followed by extension. (3) After a ∼ 20 Myr hiatus, middle Eocene to early Miocene (Lutetian-Aquitanian) accumulation of a thick succession of andesitic lavas and minor clastic sediments of the Abanico Formation occurred in an intraarc extensional basin. (4) Finally, major shortening and uplift of previously deposited Mesozoic-Cenozoic rocks took place throughout the Neogene. This phase constituted the primary contractional deformation in the Andes of south-central Chile and Argentina. In terms of the transition to early Andean deformation, we propose that structural deformation did not generate a major, regional-scale fold-thrust belt during the late Albian-Santonian. Modest extension, tectonic quiescence, or low-magnitude shortening seem to have dominated during the early to middle Cenozoic.