Humans and ecosystems are deeply connected to, and through, the hydrological cycle. However, impacts of hydrological change on social and ecological systems are infrequently evaluated together at the global scale. Here, we focus on the potential for social and ecological impacts from freshwater stress and storage loss. We find basins with existing freshwater stress are drying (losing storage) disproportionately, exacerbating the challenges facing the water stressed versus non-stressed basins of the world. We map the global gradient in social-ecological vulnerability to freshwater stress and storage loss and identify hotspot basins for prioritization (n = 168). These most-vulnerable basins encompass over 1.5 billion people, 17% of global food crop production, 13% of global gross domestic product, and hundreds of significant wetlands. There are thus substantial social and ecological benefits to reducing vulnerability in hotspot basins, which can be achieved through hydro-diplomacy, social adaptive capacity building, and integrated water resources management practices.