Freshwater resources globally are under stress due to increasing greenhouse gas emissions, rising temperatures, and anthropogenic forcing. The agricultural sector, as the largest consumer of freshwater, is particularly vulnerable to these changes. The Po river basin, Italy’s largest river basin and agrarian hub, has been experiencing frequent droughts in recent years. This study set out to provide some insights regarding the sustainable management of water resources in large river basins suffering from climate change. The specific objectives included the analysis of historical climatic trends, assessment of evapotranspiration patterns and, evaluation of aridity threats across the Po river basin on seasonal and spatial scales. Mann-Kendall and seasonal Mann-Kendall tests, combined with Theil-Sen’s slope, were applied to detect past trends and rates of change from 1960 to 2020. The classical Bandini Pluviometric classification for Italy was updated using current data to better characterize precipitation regimes. Temperature and precipitation data were altitudinally detrended to eliminate elevation influences, and updated monthly climatological maps were developed for the basin. The basin’s water demand was assessed using Thornthwaite potential evapotranspiration (indicative of ecosystem water demand as a climatic characteristic) and crop evapotranspiration obtained from the Hargreaves and Samani’s reference evapotranspiration adjusted with crop coefficients (as per Corine land cover classes). Additionally, crop evapotranspiration demand was determined for four cropping scenarios which were millet and lentils, barley and lentils, winter wheat and green beans, and rice and lentils. The spatial and temporal trends in aridity were assessed using four aridity indices based on two different aspects. Temperature and precipitation-based i.e., De Martonne and De Martonne Pinna combinative indices, and evapotranspiration-based i.e., Melisenda and Budyko aridity indices. Results showed significant increasing trends in all temperature metrics, most prominently during summer seasons with rates of 0.5 degree C to 0.7 degree C per decade. Over 80% of the basin showed higher crop evapotranspiration than potential evapotranspiration, indicating irrigation needs. While the basin is classified as humid on an annual basis, about 40% experiences Mediterranean to semi-arid conditions during summer, coinciding with peak growing season. The rice-lentils cropping system showed the highest water deficit, reaching 500 mm annually. These findings highlight the need for immediate action through sustainable strategies including crop selection, irrigation efficiency, and integrated water resources management to ensure the basin’s hydrological and agricultural sustainability.