<p>Communities are facing extreme pressure to provide safe water to the fast-growing population, especially in urban regions. Wastewater is a valuable resource which must be used to curb water shortage; otherwise, it would become a lost opportunity. However, the implementation of an effective water reuse scheme faces many techno-economic and social challenges, stressing the need for an integrated approach. This study presents a decision support framework for implementing water reuse in India by synthesizing and evaluating treatment trains for various applications. Compared to previous DSS (Decision Support System) techniques, the study integrates lifecycle cost and performance estimation using MCDM (Multi-Criteria Decision Making) technique and formulates treatment train synthesis to the Indian context. A total of 40 treatment trains have been generated for reuse in agriculture, horticulture, toilet flushing/vehicle washing, environmental, recreational, surface, and groundwater recharge. It can be observed that for agricultural reuse, the optimum treatment train is based on extended aeration followed by the tertiary process with an annual lifecycle cost of USD 3.1 billion (B)/m³/day of wastewater treatment capacity and moderate performance. The results indicate that the treatment requirement and associated life cycle costs vary with the type of reuse application. The evaluation of performance reliability and cost assessment further provides robustness to the developed approach.</p>