This paper presents a multiperiod optimization approach to the cost-effective reduction of the negative impact caused by discharging industrial effluents into watersheds. The model considers all discharges and extractions, as well as the chemical reactions carried out in the watershed, while accounting for the seasonal variability of the system through the year. The proposed model is based on a material flow analysis applied to a distributed treatment system for industrial effluents in a macroscopic water system. The problem is formulated as a multiobjective optimization model with the objectives of simultaneously minimizing the pollutant concentrations in the final catchment areas and the total annual cost of the waste-treatment units. The model selects the place to locate the treatment units and the type of treatment technology, as well as the industrial effluents treated in each period of the year, to satisfy the environmental regulations. Two case studies are presented to show the applicability of the proposed optimization approach: one is the Bahr El-Baqar drain in Egypt and the other one is the Balsas watershed in Mexico.