The Caltepec shear zone is a dextral transpressional tectonic boundary between the Oaxacan and Acatlán Complexes, which are crystalline basements of the Zapo-teco and Mixteco terranes in southern México, respectively. The terrane boundary (2–6 km wide) reveals protracted and polyphase tectonic activity from at least Early Permian to the present. The major tectonothermal event in the Caltepec fault zone was related to the oblique collision of the metamorphic complexes during the amalgamation of Pangea. An anatectic leucosome and the resulting syntectonic granite (Cozahuico Granite) in the fault zone yielded U-Pb zircon ages of 275.6 ± 1.0 Ma and 270.4 ± 2.6 Ma, respectively. The initial ⁸⁷Sr/⁸⁶Sr ratios (0.70435–0.70686) and Sm-Nd model ages (T_DM) (1.0–1.6 Ga) for the Cozahuico Granite and leucosome indicate a magmatic mixture that originated from melted Proterozoic crust and a component of depleted mantle. The Leonardian age of the cover (Matzitzi Formation) and a ⁴⁰Ar/³⁹Ar cooling age (muscovite) of 268.59 ± 1.27 Ma for mylonitic mica schist at the base of the thrust imply high cooling rates (∼180 °C/Ma) and uplift during the Permian. The adjacent sedimentological record indicates intense tectonic reactivation during Early Cretaceous, Paleogene, and Neogene along the long-lived Caltepec fault zone, alternating with periods of relative tectonic quiescence during Triassic, Jurassic, and Mid-Cretaceous times. The trend of the Caltepec fault zone parallel to the Oaxaca fault, 50 km to the east, is interpreted as part of a synchronous and dynamically coupled tectonic system that has been releasing tectonic stresses associated with the rupture of Pangea and the evolution of the Pacific margin of southern México from Jurassic to Holocene times.