Worldwide, demand for water, energy, and food are on the rise due to population and industrial growth. Because of such increasing demands and in spite of the limitedness of key resources, more efficient ways to meet these demands become obligatory. Especially considering the multiple interlinkages between water, energy, and food/livelihood systems, an integrated management of key resources such as water, land, and energy deems essential for realizing synergetic efficiencies, for consistent policy decisions, and for sustainable development, in particular across the river basins of the world. Therefore, the general framework of a system-wide economic-water-energy model (SEWEM), which is applicable across river basins and adjustable to different spatial scales such as sub-catchments, is presented here to meet the demands for an effective analytical tool in dealing with water-energy-food/livelihood nexus challenges. Previous hydro-economic models often ignored energy requirements, for instance, for irrigation water supply, as well as energy supply constraints, which recurrently might have led to an overestimation of the optimal levels of ground and surface water uses. The SEWEM was developed to address this gap and analyze how optimal levels of surface and groundwater uses, as well as on irrigation and power production benefits, change in response to the consideration of energy supply constraints and energy requirements for water pumping and other agricultural production operations. This is illustrated for the case of the Aral Sea Basin (ASB) in Central Asia, where surface and groundwater supplies heavily depend on pumping and thus on energy availability. The findings underlined the overestimations of optimal water uses by a hydro-economic model that neglects energy constraints. Moreover, geographical conditions have affected the changes in optimal ratios of surface and groundwater uses and water distributions across the river basin when energy restrictions are taken into account. The results confirmed the importance of the consideration of energy constraints for the assessment of optimal water and land uses, and the essential role of an integrated analysis of water, energy, and food/livelihood systems for better-informed policy-making. Despite the added value of the SEWEM that can consider energy system constraints, further fine-tunings would make it even more relevant for addressing additional questions related to basin management. For example, improvements can be expected through considering the system dynamics, ecological aspects, income distribution effects, trade relationships, and institutional restrictions.