Strontium isotopic ratios (⁸⁷Sr/⁸⁶Sr) in sedimentary and igneous rocks may provide valuable interpretations that allow constraining the geologic evolution of sedimentary basins. We present a new ⁸⁷Sr/⁸⁶Sr dataset from sedimentary units in the southern Central Andes (33°–34°S)—coupled to available isotopic information of igneous rocks—to examine the paleogeographic evolution of the Andes at the western margin of South America during the Mesozoic. These new data was obtained from shales, limestones and fine-grained sandstones from Mesozoic formations in the Coastal Cordillera and the Principal Cordillera of the main Andes. The new Sr-isotopic data on the Mesozoic sedimentary rocks can be grouped by both rock type and location: a) Continental red sandstones: 0.7038–0.7124; b) Calcareous rocks of the main Andes (Principal Cordillera): 0.7070–0.7081; and c) Calcareous rocks of the Coastal Cordillera: 0.7041–0.7067. The ⁸⁷Sr/⁸⁶Sr signatures in most of the clastic units in both Cordilleras are related to an evolved or enriched magmatic source for clasts and matrix indicating different sources. On the other hand, the Sr-isotopic composition of calcareous rocks differs between the units in the Andean and the Coastal mountain belts: shales and limestones in the Principal Cordillera of the Andes display ⁸⁷Sr/⁸⁶Sr ratios corresponding to the contemporary ocean in the Late Jurassic and Early Cretaceous; whereas the carbonatic units in the Coastal Cordillera do not show a relation with any oceanic signatures. The Sr-isotopic compositions of the Andean carbonatic units in the Principal Cordillera support the interpretation of their marine depositional environment in the paleo Pacific Ocean. In contrast, carbonate rock samples from the formations in the Coastal Cordillera suggest that they formed in brackish-water depositional basins made by topographic highs partially disconnected from the ocean. In the case of clastic rocks, their Sr-isotopic compositions provide insights into the contributions derived from the magmatic arc to the clastic units. Therefore, the Sr-isotopic composition of the sedimentary rocks provides a new dataset which can improve our understanding of the geological evolution of the southern Central Andes.