Socio-economic and ecological challenges faced by the small-scale fishers dependent on the Old Brahmaputra River, Bangladesh are assessed using a combination of questionnaire survey, co-monitoring of fish catch, focus group discussions and key informant interviews. Results reveal that the fishers are involved in professional, seasonal or subsistence fishing. Fish catches from the river have declined significantly because of overfishing, destructive use of fishing gear, water pollution, siltation, rapid urbanization and human encroachment, thereby threatening the health of the river ecosystem as well as the future of small-scale fishing. We evaluate various social, economic and ecological challenges faced by the fisher communities. We propose a conceptual framework that recognizes linkages among social, economic and ecological aspects in devising a sustainable river fisheries management system. We recommend effective legal enforcement of policies and regulations, strong institutional collaboration and active fisher community participation in management to ensure sustainable use of the resource base.