In this study, a new wastewater load allocation approach using a linked simulation-optimization model is proposed to determine the receiving body-based discharge limits by considering the discharge standards used by the European Union Water Framework Directive. By using the proposed approach, wastewater loads of point sources can be determined in such a way that the parameters exceeding the water quality targets (WQT) in receiving water bodies meet the relevant WQT. The simulation part is used to determine pollutant concentrations throughout the river system using the AQUATOX water quality simulation model. However, since AQUATOX is an independent simulation model and its source code is not publicly available, it is not possible to execute it with the optimization model for the generated load combinations. Therefore, a concentration-response matrix (CRM) is developed as a surrogate water simulation model by using the outputs of the AQUATOX model. After this process, the developed CRM is integrated into an optimization model where the heuristic differential evolution (DE) optimization approach is used. The performance of the proposed simulation-optimization approach is evaluated on a sub-watershed of the Kucuk Menderes River Basin by considering different waste load allocation scenarios for the CBOD5 water quality parameter. The results showed that the proposed simulation-optimization approach can effectively allocate the wastewater loads among different point sources by considering the WQT values of the CBOD5 parameter.