The Greater Mekong Subregion is a transnational area bound together by the Mekong River basin and its immense hydropower resources, historically seen as the backbone of regional economic development. The basin is now punctuated by several dams, successful in attracting both international investors and fierce criticisms for their environmental and societal impacts. Surprisingly, no attention has been paid so far to the actual performance of these infrastructures: is hydropower supply robust with respect to the hydro-climatic variability characterizing Southeast Asia? When water availability is altered, what are the implications for power production costs and CO2 emissions? To answer these questions, we focus on the Laotian–Thai grid—the first international power trade infrastructure developed in the region—and use a power system model driven by a spatially-distributed hydrological-water management model. Simulation results over a 30-year period show that production costs and carbon footprint are significantly affected by droughts, which reduce hydropower availability and increase reliance on thermoelectric resources. Regional droughts across the Mekong basin are of particular concern, as they reduce the export of cheap hydropower from Laos to Thailand. To put the analysis into a broader climate-water-energy context, we show that the El Niño Southern Oscillation modulates not only the summer monsoon, but also the power system behaviour, shaping the relationship between hydro-climatological conditions, power production costs, and CO2 emissions. Overall, our results and models provide a knowledge basis for informing robust management strategies at the water-energy scale and designing more sustainable power plans in the Greater Mekong Subregion.