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By combining long-term ground-based data on water withdrawal with climate model projections, this study quantifies the compounding effects of human activities and climate change on surface water availability in Iran over the twenty-first century. Our findings show that increasing water withdrawal in Iran, due to population growth and increased agricultural activities, has been the main source of historical water stress. Increased levels of water stress across Iran are expected to continue or even worsen over the next decades due to projected variability and change in precipitation combined with heightened water withdrawals due to increasing population and socio-economic activities. The greatest rate of decreased water storage is expected in the Urmia Basin, northwest of Iran, (varying from -8.3mm/year in 2010-2039 to -61.6mm/year in 2070-2099 compared with an observed rate of 4mm/year in 1976-2005). Human activities, however, strongly dominate the effects of precipitation variability and change. Major shifts toward sustainable land and water management are needed to reduce the impacts of water scarcity in the future, particularly in Iran's heavily stressed basins like Urmia Basin, which feeds the shrinking Lake Urmia.