The upstream construction of hydropower dams may drastically intensify climate change impacts due to changing the natural river flood-drought cycle and reducing the amount of water that flows into the lower Mekong Delta river, leading to hydrological and environmental health im-pacts. However, until now the influence of drought on residents’ health in the lower MDR, where river drought is highly sensitive to recently built hydropower plants, has not been examined. The objectives of this study are, for the first time, to detect the health impacts of river drought on residents and to evaluate the contribution of hydropower dams to the impacts of drought on health in the lower Mekong Delta Region (MDR). We applied the multi-step approaches of a Detection and Attribution study. First, we detected the effects of the river drought on the risk of hospitalization using a Multivariable Fractional Polynomials algorithm (MFP). Second, we linked the long-term changes of the river water level (RWL) to the operation of the first hydropower dam in the upper MDR using the interrupted time-series model (ITS). Finally, we quantified the hos-pitalizations and related economic loss attributed to the river drought. The results show that the percentage changes in risk of all-cause, respiratory, and renal hospitalizations attributed to the river drought were 2%, 2%, and 7%. There were significant reductions in average level and trend of the RWL during the post-1995 period, when the first hydropower dam began operation in the upper MDR, even though the cumulative rainfall in the MDR had not changed. The all-cause hospitalizations attributed to the river drought were 1134 cases during the period 1995–2014, which resulted in total additional cost at two provincial hospitals of US $360,385. This current study demonstrates the link between hydropower dams, river drought, and health impacts. As the MDR is highly vulnerable to climate change, these findings about the devastating impacts of hydropower dams and environmental change have important implications for the lives of downstream residents.