Sustainable water resource management is a wicked problem, fraught with uncertainties, an indeterminate scope, and divergent social values and interests among stakeholders. To facilitate better management of Southeast Asia’s transboundary Sesan, Sekong and Srepok (3S) River basin, we used the Freshwater Health Index (FHI) to diagnose the basin’s current and likely future level of freshwater health. We used the conditions for December 2016 as a baseline, where Ecosystem Vitality and Ecosystem Services scored 66 and 80, respectively, out of a possible 100, whilst Governance & Stakeholders scored 43. Thus, the 3S provided a range of desired ecosystem services, but there were signs of environmental stress as well as undeveloped water governance systems and limited stakeholder engagement. We also modelled four hydropower development scenarios and found that increasing development reduced the scores of a subset of indicators. This compromised the future ability of the 3S basin’s ecosystem to provide its current range of services. The FHI helped identify data deficiencies, illuminated important social dynamics, made ecosystem–human–water dynamics more understandable to stakeholders, and examined the long-term dynamics of the basin.