Due to poor water resources management, groundwater-dependent agriculture induces substantial stress on several aquifer systems worldwide, which poses a serious threat to water and food security. However, only a few studies have addressed this vital issue. This study aimed to evaluate stress on aquifers due to the overuse of groundwater for food production and explore pathways for stress reduction via improved irrigation efficiency and productivity. Groundwater stress was characterized using the ratio of water use to availability, with consideration for environmental flows. The results indicated that out of 107 countries—dependent on groundwater irrigation, about half are overexploiting groundwater, while one-fifth of these countries are extracting moderately-to heavily. Over 90% of the non-renewable groundwater abstraction occurs in 7 countries. Further, about 450 million tonnes (Mt) of global annual food production is from non-renewable groundwater exploitation. If the existing irrigation efficiency is increased to 90%, current groundwater stress would be reduced by 40%. Additionally, in unstressed regions, it would be possible to produce additional 300 Mt of food by using saved water while maintaining groundwater stress at acceptable levels. Moreover, improved water productivity in conjunction with increased irrigation efficiency could reduce the current level of unsustainable food production by 47%. These results provide important insights into the dynamics of irrigation stress on groundwater systems, and the role of managerial interventions.