We assess the sustainability of groundwater irrigation in the Euro-Mediterranean region. After analysing the available data on groundwater irrigation, we identify areas where irrigation causes groundwater depletion. To prevent the latter, we experiment with guidelines to restrict groundwater irrigation to sustainable levels, simulating beneficial and detrimental impacts in terms of improved environmental flow conditions and crop yield losses. To carry out these analyses, we apply the integrated model of water resources, irrigation and crop production LISFLOOD-EPIC. Crop growth is simulated accounting for atmospheric conditions and abiotic stress factors, including transpiration deficit. Four irrigation methods are modelled: drip, sprinkler, and intermittent and permanent flooding. Hydrologic and agricultural modules are dynamically coupled at the daily time scale through soil moisture, plant water uptake, and irrigation water abstraction and application. Water abstractions of other sectors are simulated based on requirement data. Water may be withdrawn from groundwater, rivers, lakes and reservoirs. As groundwater is abstracted to buffer the effects of drought, we use groundwater depletion to detect unsustainable water exploitation. We characterise reported data of annual groundwater abstractions for irrigation available at country and sub-national levels. Country data are the most complete, but their spatial resolution is often coarse. While the resolution of sub-national data is finer, their coverage is heterogeneous. Simulated and reported irrigation groundwater abstractions compare well in several areas, particularly in France, while some structural discrepancies emerge: simulated values tend to be larger than those reported, especially in southern Spain; and simulated inter-annual variability is significantly smaller than reported in some areas, most remarkably in Turkey. Potential causes of these discrepancies are simplified model assumptions influencing irrigation frequency and amounts; lack of high temporal and spatial resolution data on irrigated areas, and irrigation technologies and distribution; and possible unreported abstractions in areas where groundwater irrigation is significant. We identify areas undergoing groundwater depletion from model simulations. In the southern Iberian Peninsula, Greece, Middle East and northern Africa, most simulated depletion is caused by irrigation. In other Mediterranean areas, depletion is caused by all sectors combined. From well measurements of groundwater table depth in Spain, we find statistically significant decline rates affecting large areas of the south, thus in agreement with the model, but also areas in the north-eastern and central parts where model estimates detect no depletion. The comparison of model- and well-based depletion rates is limited by spatial scale differences and groundwater model assumptions, for which we suggest potential research directions. We design rules restricting irrigation groundwater abstraction to prevent groundwater depletion and minimise severe irrigation shortages. We optimise them and simulate their effects in the southern Iberian Peninsula. Irrigation restrictions cause crop yield reductions in groundwater-dependent irrigated areas, particularly in the Algarve and Segura river basin districts. At the same time, they positively impact environmental flows. This study shows the potential of integrated agro-hydrologic modelling for detecting water resources over-exploitation and exploring trade-offs between crop production, sustainable irrigation and ecosystem support.