Anthropogenic climate change and increased human water use are widely expected to place great stress on available water resources across Africa and Madagascar, but the effects of these changes on freshwater biodiversity have only begun to be considered. We used a comprehensive species database and a global hydrologic model to examine the exposure of freshwater biodiversity to discharge and runoff alterations across Africa and Madagascar. Our results show that by the 2050s, ecoregions containing over 80% of freshwater fish species and several outstanding ecological and evolutionary phenomena are likely to experience hydrologic conditions substantially different from the present, with alterations in annual discharge or runoff of more than 10%. We recommend early action to buffer these species and systems from the expected changes, including reducing non-climate stresses and implementing measures that buy species time to adjust to novel ecosystem characteristics.