Future climate projections robustly indicate that the Mediterranean region will experience a significant decrease of mean annual precipitation and an increase in temperature. These changes are expected to seriously affect the hydrologic regime, with a limitation of water availability and an intensification of hydrologic extremes, and to negatively impact local economies. In this study, we quantify the hydrologic impacts of climate change in the Rio Mannu basin (RMB), an agricultural watershed of 472.5 km[superscript 2] in Sardinia, Italy. To simulate the wide range of runoff generation mechanisms typical of Mediterranean basins, we adopted a physically based, distributed hydrologic model. The high-resolution forcings in reference and future conditions (30-year records for each period) were provided by four combinations of global and regional climate models, bias-corrected and downscaled in space and time (from ~25 km, 24 h to 5 km, 1 h) through statistical tools. The analysis of the hydrologic model outputs indicates that the RMB is expected to be severely impacted by future climate change. The range of simulations consistently predict (i) a significant diminution of mean annual runoff at the basin outlet, mainly due to a decreasing contribution of the runoff generation mechanisms depending on water available in the soil; (ii) modest variations in mean annual runoff and intensification of mean annual discharge maxima in flatter sub-basins with clay and loamy soils, likely due to a higher occurrence of infiltration excess runoff; (iii) reduction of soil water content and actual evapotranspiration in most areas of the basin; and (iv) a drop in the groundwater table. Results of this study are useful to support the adoption of adaptive strategies for management and planning of agricultural activities and water resources in the region.