The levels of cooperation in efforts towards transboundary water management in the Aral Sea basin have ranged from high to low over the past few decades, due in part to diverse purposes for water use in the region. Two important and often conflicting uses are agriculture and hydropower, which tend to align by sector with national boundaries. Successful management and development of water resources of the Amu-Darya River, one of the two main rivers of the basin, will require building closer cooperation among states. Improvement in cooperative efforts, in turn, will require both water supply-oriented infrastructure development (such as dams and reservoirs), and demand-oriented infrastructure development (such as improvement of water conveyance in irrigation canals). The goal of this research was to evaluate four alternative scenarios for water, energy, and food security that could be achieved by the riparian states, as well as the sustainability dimensions of development of these infrastructures. The four scenarios were based on different combinations of infrastructure development, operational modes of upstream reservoirs, and piping of irrigation canals. For this purpose, the Interdisciplinary Nexus Sustainability Assessment Framework (INSAF) was developed that incorporates assessment of changes in WEF security for riparian states and Bio-physical, Socio-economic, and Geo-political dimensions of infrastructure development in the Amu-Darya River basin. The results of the research indicate that application of both a supply and demand management approach to water resources management and development increases the “basket of benefits” for water, energy, and food security achievements, and has a potential to improve cooperation and sustainable basin development by reducing tensions linked with water allocation and timing of water use in the basin.