Many of the world's major freshwater aquifers are being exploited unsustainably, with some projected to approach environmentally unsafe drawdown limits within the 21st century. Given that aquifer depletion tends to occur in important crop producing regions, the prospect of running dry poses a significant threat to global food security. Here we use the Global Change Assessment Model (GCAM) to explore the response of land use and agriculture sectors to severe constraints on global water resources. We simulate a scenario in which a number of important groundwater aquifers become depleted to the point where further water withdrawal is unviable, either due to excessive extraction costs or environmental limits being reached. Results are then benchmarked against a scenario that neglects constraints on water withdrawals. We find that groundwater depletion and associated water price increases drive two distinct responses in the agriculture sector: an expansion of rain fed agriculture, and a shift in irrigated crop production toward regions with cheaper water resources. Losses in crop production are most pronounced in water stressed regions where groundwater is being depleted unsustainably to meet irrigation demands—namely northwest India, Pakistan, the Middle East, western United States, Mexico, and Central Asia. While these results highlight substantial risks for the affected regional agricultural economies, we show that modest changes in irrigation and location of crop growth, in a world with frictionless trade, could ensure global food demands are met despite severe water constraints.