Large reservoirs in the tropics act as efficient nutrient traps and often develop hypoxic conditions in the hypolimnion. Both effects may have severe implications for aquatic ecosystems, such as limited primary production in downstream riparian agriculture and in natural wetlands due to reduced nutrient loads, and, if hypolimnetic waters are withdrawn, hypoxic conditions that pose toxic risks in downstream rivers. This study using Itezhi-Tezhi Reservoir (Zambia) as a model system aims at defining optimized turbine withdrawal to prevent hypoxia and to relieve low-nutrient conditions in the downstream Kafue Flats floodplain. A biogeochemical 1-D model simulating reservoir-internal processes and water quality in the outflow was used for estimating dissolved oxygen (DO) concentrations and inorganic nitrogen and phosphorus loads in the outflow. The water depth of turbine withdrawals was varied in a set of simulations to optimize outflow water quality. Releasing hypolimnetic water was shown to result in lower average outflow DO concentrations of 4.1–6.8 mg l−1 compared to the current 7.6 mg l−1. More importantly, the outflow will remain hypoxic during up to 189 days. Meanwhile, withdrawing nutrient-rich hypolimnetic water compensated effectively for nutrient losses to the reservoir sediment. Both outflow DO concentrations and nutrient output could be optimized in the scenario with 50% epilimnetic turbine discharge originating from ∼13 m depth. In this optimal scenario, hypoxia was prevented permanently, and average DO concentrations decreased moderately to 5.2 mg l−1. Additionally, five-times higher dissolved inorganic N and dissolved inorganic P loads resulted in comparison to the current dam operation.