The transboundary Mekong Basin has been dubbed the “Battery of Southeast Asia” for its large hydropower potential. Development of hydropower dams in the six riparian countries proceeds without strategic analyses of dam impacts, e.g., reduced sediment delivery to the lower Mekong. This will impact some of the world’s largest freshwater fisheries and endangers the resilience of the delta, which supports 17 million livelihoods, against rising sea levels. To highlight alternatives, we contribute an optimization-based framework for strategic sequencing of dam development. We quantify lost opportunities from past development and identify remaining opportunities for better tradeoffs between sediment and hydropower. We find that limited opportunities remain for less impactful hydropower in the lower basin, where most development is currently planned, while better trade-offs could be reached with dams in the upper Mekong in China. Our results offer a strategic vision for hydropower in the Mekong, introduce a globally applicable framework to optimize dam sequences in space and time, and highlight the importance of strategic planning on multiple scales to minimize hydropower impacts on rivers.