The Brahmaputra is one of the largest river systems of South Asia, providing life-supporting services to about 70 million people. Massive flooding, land erosion, over-exploitation of water, excessive fishing, habitat degradation and fragmentation, exploitation of flood plains, climate change impacts, absence of integrated basin wide management, and transboundary cooperation are major challenges for the present and future sustainability and development in the basin. Although hydrological connectivity is intact in most of the main course of the river, the infrastructure development plans may convert the Brahmaputra to a predominantly managed river system. In this regard, this paper examines the physiographic, ecological, hydrological, and socioeconomic status of the Brahmaputra river, its transnational basin in South Asia, and the basin population in the cross-cutting context to explore its sustainable management options. For a durable future of the river and its communities, an integrated management mechanism among the basin countries with the objective of equitable benefit sharing, disaster risk management, and resilience building is needed. The suggested strategies will help in maintaining the ecohydrological health and utilitarian services of the river for the socioeconomic development of millions of poor and marginalized people living in the basin.