Helleh River, a southern vital agricultural ecosystem in Iran, has been suffering from both water shortage and quality degradation in recent decades. To deal with the problems, different stakeholders have been suggesting the central government some compartment development plans including construction of dams and irrigation districts, installation of modern irrigation technologies, and modification of crop patterns and irrigation–leaching strategies. Accordingly, this paper proposes a generic novel hydro-economic methodology for basin-scale optimal planning of an integrated development scheme for Helleh River Basin. Mentioned measures in different spatial scales from farm-level to basin-level as well as distinct time horizons of short-term and long-term are holistically evaluated and optimized based on technical, hydrologic, agronomic, and economic aspects. In this regard, a water allocation simulation model, i.e. WEAP software, improved here by some extra modules for salt routing and economic evaluation in Python Programming Environment is coupled with an optimization algorithm, i.e. Particle Swarm Optimization, which results in a new holistic hydro-economic simulation–optimization tool. Results demonstrate the economic efficiency of constructing three new dams, improvement and development of 19930 ha (ha) of irrigation area, irrigation technology, and strategy change, and crop pattern modification. Furthermore, results show that optimizing irrigation–leaching schedule leads to significant improvement of the economic value of water compared to the status quo, while construction and operation of structural projects result in a dramatic decrease in the economic value of water due to increase in both costs and leaching-related water usage. We discuss how irrigation technology improvement in salinity-affected basin may lead to a decrease in the economic value of water. Moreover, we advocate for the application of deficit irrigation strategy while respecting salt leaching requirements and cultivation of lower water-consuming crops. Results demonstrate how reservoirs’ operation takes a minor role in the regulation of rivers’ salinity, while we anticipate a significant increase in salt concentration of crops’ root zones due to more efficient water use.