River flow dynamics play an important role for aquatic and riparian ecosystems. Climate change is projected to significantly alter river flow regimes in Europe and worldwide. In this study, we evaluate future river flow alterations in the entire Danube River basin by means of ecologically relevant river flow indicators under different climate warming scenarios (Representative Concentration Pathway (RCP) 2.6, RCP 4.5, and RCP 8.5). The process-based watershed model SWIM was applied for 1124 sub-catchments to simulate daily time series of river discharge for the Danube River and its tributaries under future scenario conditions. The derived hydrological data series were then statistically analyzed using eight eco-hydrological indicators to distinguish intra-year variations in the streamflow regime. The results are used to: (a) analyze the possible impacts of climate change on the ecologically relevant flow regime components; and (b) identify regions at the highest risk of climate change-driven flow alterations. Our results indicate that climate change will distinctively alter the recent ecological flow regime of the Danube River and, in particular, the tributaries of the Middle and Lower Danube basin. While for the RCP 2.6 scenario the projected flow alterations might still be considered moderate for many rivers, the impacts might strongly accelerate if global mean temperatures rise more than 2 °C compared to pre-industrial times. Under RCP 4.5 and RCP 8.5 warming scenarios, the recent ecological flow regime might be highly altered, posing a serious threat to river and floodplain ecosystems.