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Groundwater depletion is an important problem driven by population growth, land use and land cover (LULC) change, climate change, and other factors. Groundwater depletion generates water stress and encourages unstainable resource use. The aim of this study is to determine how population growth, LULC change, and climate change relate to groundwater depletion in the Alto Atoyac sub-basin, Oaxaca, Mexico. Twenty-five years of dry season water table data from 1984 to 2009 are analyzed to examine annual groundwater depletion. Kriging is used to interpolate the region's groundwater levels in a geographic information system (GIS) from mapped point measurements. An analysis of remotely sensed data revealed patterns of LULC change during a 34-year (1986-2018) period, using a supervised, machine-learning classification algorithm to calculate the changes in LULC. This analysis is shown to have an 85% accuracy. A global circulation model (GFDL-CM3) and the RCP4.5 and RCP8.5 scenarios were used to estimate the effects of climate change on the region's groundwater. Estimates of evapotranspiration (using HELP3.5 code) and runoff (USDA-SCS-CN), were calculated. Since 1984, the region's mean annual temperature has increased 1.79 degrees C and urban areas have increased at a rate of 2.3 km(2)/year. Population growth has increased water consumption by 97.93 x 10(6) m(3)/year. The volume of groundwater is shrinking at a rate of 284.34 x 10(6) m(3)/year, reflecting the extreme pressure on groundwater supply in the region. This research reveals the nature of the direct impacts that climate change, changing LULCs, and population growth have in the process of groundwater depletion.