The causes of recent hydrological droughts and their future evolution under a changing climate are still poorly understood. Banking on a 216-year river flow time series at the Po River outlet, we show that the 2022 hydrological drought is the worst event (30% lower than the second worst, with a six-century return period), part of an increasing trend in severe drought occurrence. The decline in summer river flows (-4.14 cubic meters per second per year), which is more relevant than the precipitation decline, is attributed to a combination of changes in the precipitation regime, resulting in a decline of snow fraction (-0.6% per year) and snowmelt (-0.18 millimeters per day per year), and to increasing evaporation rate (+0.013 cubic kilometers per year) and irrigated areas (100% increment from 1900). Our study presents a compelling case where the hydrological impact of climate change is exacerbated by local changes in hydrologic seasonality and water use.