Climate change and intensive hydropower development pose serious challenges to the sustainable water supply of natural and social systems. This study’s purpose is to statistically esti-mate the complex influence of these factors on the Prut River flow. Its methodical approach is based on a comparative analysis of the flow in 1961–1990 and 1991–2018, reflecting the regional climate before and after an intensive global warming onset, and in 1950–1975 and 1980–2017, before and after the construction of the Stanca‐Costesti hydropower plant (HPP) on the Prut’s riverbed. The compared statistics include annual, seasonal and monthly averages and trends of climatic and hydrological parameters for each period. Since the 1990s a statistically significant increase has been demonstrated in the basin‐wide annual mean, maximum and minimum temperatures, of 1.04, 1.11 and 1.21 °C, respectively. Negative trends of annual precipitation were negligibly small and statistically insignificant in both periods (−2.1 mm and −0.6 mm/year, respectively), with annual totals differing by 1.4 mm. The seasonal transformation and changes of the Prut river flow, showing a small annual increase in the period 1961–1990 and a 1.8% decrease over next decades, are in good agreement with variability patterns of temperature (positive tendencies) and precipitation (negative tendencies). The operation of mean‐capacity HPP has no significant impact on the total water dis-charge downstream, but modifies the seasonal distribution of the river’s streamflow.