Uplift of the central Andes during the Miocene was followed by large-scale reorganization of Atlantic-draining rivers in Argentine Patagonia. Here, we document the abandonment of one large river in the late Pliocene and the establishment of the modern drainage in the Early Pleistocene. A chronology for these events is provided by ⁴⁰Ar/³⁹Ar ages on basalt flows. Remnants of the Pliocene paleovalley system are well preserved in the Lago Cardiel–Gobernador Gregores area, where they are eroded into flat-lying basalt flows dated from ca. 13.9 Ma to 8.6 Ma. Younger basalts that erupted onto the abandoned floor of the paleovalley are as young as 3.7 Ma. Abandonment of the Pliocene paleovalley and establishment of the modern Río Chico and Río Shehuen catchments happened near the close of the Pliocene when Andean glaciers incised the east-sloping pediment on which the late Miocene drainage was established. Lago Cardiel sits within a large endorheic basin that is inset into the late Pliocene paleovalley. The basin began to develop just before 4 Ma, after the paleovalley was abandoned. It became larger and deeper during the Pleistocene due to mass movements along its margins, deflation of the basin floor during times when Lago Cardiel was dry or nearly dry, and possibly lowering along bounding faults. The Pliocene–Pleistocene landscape and drainage changes that we have documented are not unique to the Lago Cardiel–Gobernador Gregores area; similar changes are apparent elsewhere in Patagonia east of the crest of the Andes.