Sustainably managing resources in a transboundary freshwater basin is a complex problem, particularly when considering the compounding impacts of climate change, hydropower development, and evolving water governance paradigms. In this study, we used a mixed methods approach to analyze potential impacts of climate change on regional hydrology, the ability of dam operation rules to keep downstream flow within acceptable limits, and the present state of water governance in Laos, Vietnam, and Cambodia. Our results suggest that future river flows in the 3S river system could move closer to natural (i.e., pre-development) conditions during the dry season and experience increased floods during the wet season. This anticipated new flow regime in the 3S region would require a shift in the current dam operations, from maintaining minimum flows to reducing flood hazards. Moreover, our Governance and Stakeholders survey assessment results revealed that existing water governance systems in Laos, Vietnam, and Cambodia are ill-prepared to address such anticipated future water resource management problems. Our results indicate that the solution space for addressing these complex issues in the 3S river basins will be highly constrained unless major deficiencies in transboundary water governance, strategic planning, financial capacity, information sharing, and law enforcement are remedied in the next decade. This work is part of an ongoing research partnership between the National Aeronautical and Space Agency (NASA) and the Conservation International (CI) dedicated to improving natural resources assessment for conservation and sustainable management.