Rice production in Cambodia, essential to food security and exports, is largely limited to the wet season. The vast majority (96%) of land planted with rice during the wet season remains fallow during the dry season. This is in large part due to lack of irrigation capacity, increases in which would entail significant consequences for Cambodia and Vietnam, located downstream on the Mekong River. Here we quantify the extent of the dry season “deficit” area in the Cambodian Mekong River catchment, using a recent agricultural survey and our analysis of MODIS satellite data. Irrigation of this land for rice production would require a volume of water up to 31% of dry season Mekong River flow to Vietnam. However, the two countries share an aquifer system in the Mekong Delta, where irrigation demand is increasingly met by groundwater. We estimate expansion rates of groundwater-irrigated land to be >10% per year in the Cambodian Delta using LANDSAT satellite data and simulate the effects of future expansion on groundwater levels over a 25-year period. If groundwater irrigation continues to expand at current rates, the water table will drop below the lift limit of suction pump wells, used for domestic supply by >1.5 million people, throughout much of the area within 15 years. Extensive groundwater irrigation jeopardizes access for shallow domestic water supply wells, raises the costs of pumping for all groundwater users, and may exacerbate arsenic contamination and land subsidence that are already widespread hazards in the region.