Organic matter and nutrient loading into aquatic ecosystems affects ecosystem structure and function and can result in eutrophication and hypoxia. Hypoxia is usually attributed to anthropogenic pollution and is rarely documented in unpolluted systems, particularly in rivers. Here we show that organic matter loading from hippopotami causes the repeated occurrence of hypoxia in the Mara River, East Africa. We documented 49 high flow events over three years that caused dissolved oxygen decreases, including 13 events resulting in hypoxia, and 9 fish kills over five years. Evidence from experiments and modeling demonstrates a strong mechanistic link between the flushing of hippo pools and decreased dissolved oxygen. This phenomenon may have been more widespread throughout Africa before hippo populations were severely reduced. Frequent hypoxia may be a natural part of tropical river ecosystem function, which directly challenges our notions of the reference state of rivers in the absence of human influence.