Bangladesh, Bhutan, India, and Nepal in the Eastern Himalayas are interconnected by the common river systems of the Ganges, Brahmaputra, and Meghna (GBM). The GBM basin is home to approximately 700 million people, comprising over 10% of the world's population. The economy and environment of the region depend on water, but while the need for water is increasing, poor management and climate-related effects are making water supplies erratic. Upstream–downstream interdependencies necessitate developing a shared river system in an integrated manner through collaboration of the riparian countries. This paper examines the opportunities for, and potential benefits of, regional cooperation in water resource management. It suggests that the benefits can increase considerably when a regional (river basin) perspective is adopted that promotes optimum use of water resources for consumptive and non-consumptive use. Regional cooperation can bring additional economic, environmental, social, and political benefits through multi-purpose river projects, which help by storing monsoon water, mitigating the effects of floods and droughts, augmenting dry season river flows, expanding irrigation and navigation facilities, generating hydropower, and enhancing energy and environmental security. A broader framework to facilitate regional cooperation in transboundary rivers in the Eastern Himalayan region is suggested.