The Mekong River Basin, site of the biggest inland fishery in the world, is undergoing massive hydropower development. Planned dams will block critical fish migration routes between the river's downstream floodplains and upstream tributaries. Here we estimate fish biomass and biodiversity losses in numerous damming scenarios using a simple ecological model of fish migration. Our framework allows detailing trade-offs between dam locations, power production, and impacts on fish resources. We find that the completion of 78 dams on tributaries, which have not previously been subject to strategic analysis, would have catastrophic impacts on fish productivity and biodiversity. Our results argue for reassessment of several dams planned, and call for a new regional agreement on tributary development of the Mekong River Basin.