While the impact of climate change on crop yields has been extensively studied, the quantification of water shortages on irrigated crop yields has been regarded as more challenging due to the complexity of the water resources management system. To investigate this issue, we integrate a crop yield reduction module and a water resources model into the MIT Integrated Global System Modeling (IGSM) framework, an integrated assessment model that links a model of the global economy to an Earth system model. While accounting for uncertainty in climate change, we assess the effects of climate and socio-economic changes on the competition for water resources between industrial, energy, domestic and irrigation; the implications for water availability for irrigation; and the subsequent impacts on crop yields in the US by 2050. We find that climate and socio-economic changes will increase water shortages and strongly reduce irrigated crop yields in specific regions (mostly in the Southwest), or for specific crops (i.e. cotton and forage). While the most affected regions are usually not major crop growers, the heterogeneous response of crop yield to global change and water stress suggests that some level of adaptation can be expected, such as the relocation of cropland area to regions where irrigation is more sustainable. Finally, GHG mitigation has the potential to alleviate the effect of water stress on irrigated crop yields—enough to offset the reduced CO2 fertilization effect compared to an unconstrained GHG emission scenario.