Canyon incision into mountain topography is commonly used as a proxy for surface uplift driven by tectonic or geodynamic processes, but climatic changes can also instigate incision. The similar to 1250-kilometer (km)-long eastern margin of the Andean Plateau hosts a series of 1.5- to 2.5-km-deep canyons that cross major deformation zones. Using (U-Th)/He thermochronology, we document a transition from Miocene faulting to Pliocene canyon incision across the northeastern plateau margin. Regionally, widespread Pliocene incision into the eastern plateau margin is concurrent with a shift in global climate from early Pliocene warmth to late Pliocene cooling. Enhanced moisture transport onto the Andean Plateau driven by sea surface temperature changes during cooling is the likely pacemaker for canyon incision.