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Numerous hydropower facilities are under construction or planned in tropical and subtropical rivers worldwide. While dams are typically designed considering historic river discharge regimes, climate change is likely to induce large-scale alterations in river hydrology. Here we analyze how future climate change will affect river hydrology, electricity generation, and economic viability of > 350 potential hydropower dams across the Amazon, Earth’s largest river basin and a global hotspot for future hydropower development. Midcentury projections for the RCP 4.5 and 8.5 climate change scenarios show basin-wide reductions of river discharge (means, 13 and 16%, respectively) and hydropower generation (19 and 27%). Declines are sharper for dams in Brazil, which harbors 60% of the proposed projects. Climate change will cause more frequent low-discharge interruption of hydropower generation and less frequent full-capacity operation. Consequently, the minimum electricity sale price for projects to break even more than doubles at many proposed dams, rendering much of future Amazon hydropower less competitive than increasingly lower cost renewable sources such as wind and solar. Climate-smart power systems will be fundamental to support environmentally and financially sustainable energy development in hydropower-dependent regions.