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Demands on freshwater for human use are increasing globally, but water resource development (WRD) has substantial downstream impacts on fisheries and ecosystems. Our study evaluates trade-offs between WRDs and downstream ecosystem functioning considering alternative dam and water extraction options, diverse eco-hydrological responses and catchment-to-coast connectivity. We used a data-driven ensemble modelling approach to quantify the impacts of alternative WRDs. WRD impacts varied from weakly positive to severely negative depending on species, scenario and cross-catchment synergies. Impacts on fishery catches and the broader ecosystem (including mangroves) increased with catchment developments and volume of water removed, or if flow reduced below a threshold level. We found complex, linked-catchment dependence of banana prawns on flow and floods. Economic risks for this important fishery more than doubled under some scenarios. Sawfish emerged as the most sensitive across a range of WRD scenarios. Our findings highlight the need to consider marine ecosystems and fisheries to inform sustainable management of the world’s remaining free-flowing rivers.