This study evaluates the effect of climate on facies, grain size, and sedimentation rates using sedimentology, geochronology, and stable isotope geochemistry for Miocene–Pliocene deposits in the Angastaco basin (Eastern Cordillera, northwest Argentina). U-Pb zircon data from ash layers constrain the transition between the finer grained fluvial-lacustrine Palo Pintado Formation and the coarser grained fluvial-alluvial San Felipe Formation to ca. 5.2 Ma and the first deposition of sediment derived from the present-day orographic barrier to ca. 4 Ma. δ13C values from pedogenic carbonate nodules range from −15.4‰ to −10.2‰ for the Palo Pintado Formation and from −9.5‰ to −8.2‰ for the San Felipe Formation; this can be best explained by increased, sustained aridity since ca. 5 Ma. The δ18O values range from −9.6‰ to −5.9‰ for the Palo Pintado Formation and from −6.1‰ to −5.2‰ for the San Felipe Formation, corroborating this interpretation. The shift toward more arid conditions correlates with a significant increase in grain size but no significant change in sedimentation rate. Because aridity precedes the development of an orographic effect, we interpret the grain size increase in the Angastaco basin since ca. 5 Ma to be a response of the sedimentary system to aridification resulting from regional climate change.