The Ganges, Brahmaputra, and Meghna (GBM) river system flows through five countries – Bangladesh, Bhutan, China, India, and Nepal – characterized by large population, limited land resources, and frequent floods and natural hazards. Although the GBM region is well endowed with water sources, this is one of the poorest regions in the world. Its economy and human and environmental health depend on water, and water is thus at the heart of sustainable development, economic growth, and poverty reduction. This paper examines the opportunities for, and potential socio-economic benefits of, water resource management in the GBM region in the face of changing climate. It argues that water can be an entry point for addressing challenges common to the region, particularly through multi-purpose river projects that store monsoon water, mitigate the effects of floods and droughts, augment dry season river flows, expand irrigation and navigation facilities, generate hydropower, and enhance energy and environmental security. The paper emphasizes the importance of effective regional cooperation in water management to achieve these benefits. Upstream–downstream interdependencies necessitate development of a shared river system in an integrated and collaborative manner.