This multidisciplinary study focuses on projecting and adapting to future hydrological changes in the Mekong – an international river of global significance in terms of rapidly increasing human pressures and climate-change vulnerability. A modelling framework was developed to project future changes in both the river flow regime and hydrological extremes (i.e. high/low flows and floods), under multiple scenarios of climate change, irrigation and hydropower developments. Furthermore, we developed a combined quantitative-qualitative approach to develop suitable adaptation measures and strategies to future floods in the Mekong Delta being a key vulnerability hotspot. Results show that the Mekong’s future flow regime is subjected to substantial changes under climate change and human developments. Climate change will intensify the hydrological cycle, resulting in increasing average river flows (between +5 % and +16%, annually), and more frequent and extreme high flows during the wet season. Flow regime shows substantial alterations in the seasonal flow distributions under the combined impacts of climate change, irrigation expansions and hydropower developments. While dry season flows increase strongly (monthly changes up to +150%), wet season flows show contrasting changes with reductions during June - October (up to -25%) and substantial increases during November – December (up to 36%). A follow-up modelling assessment for the Mekong Delta shows substantial increases in flood hazards under climate change and sea level rise, shown by higher flood frequencies and flood depths across the whole delta. Increasing flood hazards therefore represents a key issue to be addressed in terms of future adaptation. The adaptation appraisal study further shows that effective adaptation requires looking beyond sole infrastructural investments. Instead, technological innovations for flood risk management combined with improved governance and institutional capacities offer ample opportunities to adapt to future hydrological changes. This study projects substantial future hydrological changes under future climate change and accelerating socioeconomic developments and shows potentially serious consequences for water related safety and sustainable water resources uses and allocations. Furthermore, this study demonstrates amble opportunities to manage future changes through strategic development planning and through adaptive interventions. Insights from this study address the needs for quantified future hydrological changes and emphasize adequate adaptation to the associated risks in an important international river experiencing climate change and rapid socioeconomic developments.