The morphological evolution of the basins in the Sierra Madre del Sur (SMS), southern México is poorly understood. This work explains for the first time the geomorphological development of the tectonic, fluvially-interconnected SMS basins named San Juan Raya (SJRb) and Zapotitlán (ZAPb). The evolution of the SJRb and ZAPb are analysed within the context of the transformations of the well-studied Tehuacán basin (TEHb). A new interpretation of a series of tectonic features of the TEHb valley area is also presented. Published geological data and extensive field work provided the basis for our geomorphological and evolutionary interpretation of basin evolution of this part of Mesoamerica during the late Cenozoic. Stratigraphic and sedimentary records suggest that after the late Cretaceous-early Cenozoic orogeny the TEHb and ZAPb were closed basins, and that the TEHb graben system was activated during the Paleogene as a response to the dominant regional NW-SE trending faults. We propose that the ZAPb and SJRb formed sequentially during the Neogene as a result of new E-W, N-S and NE-SW faults. The continuation of the TEHb extension during the Oligocene widened its lowland area and allowed the formation of an extensive lake. No alluvial or fluvial records of this interval are found in the ZAPb and SJRb. No sedimentation rather than formation and subsequent erosion of such sediments is supported by the basin morphology and by the absence of re-worked alluvial deposits at the outlet area where both connect to the TEHb. By middle to late Miocene the TEHb lost its endorheic configuration, ending the lake-type deposition while new faults initiated the opening of the ZAPb. Intensive tectonics, alluvial deposition and the confinement of the Tehuacán lake to the north sector of this basin characterised the Pliocene. During the late Pliocene to the early Pleistocene the formation of the SJRb was initiated. Quaternary faulting related to basin extension along the north watershed of the SJRb and ZAPb is supported by independent data on the biogeography of the cactus Mammillaria pectinifera. We introduce the idea that the departure from the regional NW-SE fault alignment that formed the major Miocene basins to a more local E-W trend that formed Neogene-Quaternary basins was probably a response to the latest post-orogenic relaxation of the crust in the Mixteca terrane.