To simulate and quantify the impacts of climate change on phytoplankton dynamics and oxygen budget, a model-based approach is chosen. The 1D hydraulic model HYDRAX is coupled to the water quality model QSim (Quality Simulation). The coupled models are applied to the German section of the Elbe River and its estuary. A long-term run (1998–2010) has been performed to represent the phytoplankton dynamics and the oxygen concentrations for the reference state. The impacts of altered river discharge and air temperature on the water quality have been calculated by a model-based sensitivity analysis. A range of feasible projections of river discharge and air temperature for near (years 2021–2050) and far future (years 2071–2100) has been related to the results of the sensitivity analysis. A decrease in river discharge enhances oxygen deficits in the Elbe Estuary, while an increase in air temperature has a less pronounced and partly reverse effect.