Understanding and predicting the future vulnerability of freshwater resources is a major challenge with important societal implications. Many studies have identified Asia as a hotspot of severe water stress in the coming decades, and also highlighted the large uncertainty associated with water resource assessment based on limited multi-model projections. Here we provide a more comprehensive risk-based assessment of water use and availability in response to future climate change, socioeconomic growth, and their combination in Southern and Eastern Asia. We employ a large ensemble of scenarios that capture the spectrum of regional climate response as well as a range of economic projections and climate policies in a consistent, integrated modeling framework. We show that economic growth increases water stress ubiquitously. The climate-only and combined climate-growth effects on water stress remain largely negative in China and Indus Basin, but largely positive in India, Indochina, and Ganges Basin. However, climate poses substantially large uncertainty in water stress changes than socioeconomic growth. By 2050, socioeconomic growth alone can lead to an additional 650 million people living under at least “heavy” water stress, with most of these located in India, Indus Basin, and China. The combined effects of socioeconomic growth and climate change reduce people under water stress to an additional 200 million, attributed mainly to the beneficial climate in India that moves its heavily-stressed condition into the slightly or moderately‑stressed conditions. These 200 million people primarily reside in Indus Basin and China under at least overly exploited water conditions— where total water requirements will consistently exceed surface water supply. Climate mitigation helps alleviating the risks of increasing water scarcity by midcentury, but to a limited extent. Therefore, adaptive measures need to be taken to meet these surface water shortfalls, or a combination of both approaches may be most effective.