This study analyzes effects of climate change (CCh) and of the increase of impervious surfaces on the groundwater recharge in the Alto Atoyac sub-basin (Oaxaca, southern Mexico). Water recharge was modeled based on HELP 3.95D; temperature and precipitation were derived, for a near (2015–2039) and a far distant future scenario, from GFDL-CM3 global circulation model (GCM), which describes the climate of Mexico under the RCP8.5 scenario. Potential recharge loss zones for the period of 1979–2013 were estimated through a remote sensing analysis. The actual estimated mean annual recharge of 169 million cubic metres could be reduced by 17.97% and 65.09% according to the analyzed CCh scenarios, and the loss of 135 km2 of permeable soil would represent additionally 2.65 × 106 m3 of non-infiltrated water. This study indicates three sites, with high recharge potential, and it can be used to propose local adaptations to guarantee the availability of the water resource in the studied sub-basin.