The Water-Energy-Food-Ecosystem (WEFE) nexus concept postulates that water, energy production, agriculture and ecosystems are closely interlinked. In transboundary river basins, different sectors and countries compete for shared water resources. In the Danube River Basin (DRB), possible expansion of agricultural irrigation is expected to intensify water competition in the WEFE nexus, however, trade-offs have not yet been quantified. Here, we quantified trade-offs between agriculture, hydropower and (aquatic) ecosystems in the DRB resulting from maize irrigation when irrigation water was withdrawn from rivers. Using the process-based hydro-agroecological model PROMET, we simulated three maize scenarios for the period 2011–2020: (i) rainfed; (ii) irrigated near rivers without considering environmental flow requirements (EFRs); (iii) irrigated near rivers with water abstractions complying with EFRs. Maize yield and water use efficiency (WUE) increased by 101–125 % and 29–34 % under irrigation compared to rainfed cultivation. Irrigation water withdrawals from rivers resulted in moderate to severe discharge reductions and, without consideration of EFRs, to substantial EFR infringements. Annual hydropower production decreased by 1.0–1.9 % due to discharge reductions. However, the financial turnover increase in agriculture (5.8–7.2 billion €/a) was two orders of magnitude larger than the financial turnover decrease in hydropower (23.9–47.8 million €/a), making water more profitable in agriculture. Irrigation WUE was highest for EFR-compliant irrigation, indicating that maintaining EFRs is economically beneficial and that improving WUE is key to attenuating nexus water competition. Current maize production could be met on the most productive 35–41 % of current maize cropland under irrigation, allowing 59–65 % to be returned to nature without loss of production. Maize priority areas were on fertile lowlands near major rivers, while biodiversity priority areas were on marginal cropland of highest biodiversity intactness. Our quantitative trade-off analysis can help identifying science-based pathways for sustainable WEFE nexus management in the DRB, also in light of climate change. Display omitted •Trade-offs in the water-energy-food-ecosystem nexus are quantified in Danube basin.•Process-based modelling of maize irrigation scenarios assuming river water extraction.•Revenue gain in agriculture exceeds loss in hydropower; land can be saved for nature.•Moderate to severe river runoff reduction; environmental flow maintenance pays off.•High agricultural (irrigation) water use efficiency reduces nexus water competition.