The pervasive presence of plastics in the environment and their increasing release into natural ecosystems represent a significant concern for both human and environmental health. Wastewater Treatment Plants (WWTPs) are identified as a primary source for plastics to enter water courses. Although various studies have demonstrated the efficiency of certain coagulants/flocculants in removing plastics from wastewater in laboratory tests, their potential application in WWTPs remains under-explored, and numerous commercial polymer-based flocculants have not yet been tested. To address this gap, the aim of this study is the evaluation of the effectiveness of different commercial polymer-based flocculants, synthetic and natural, to decrease the plastic concentration in wastewater. To assess their effectiveness across different matrices and mixtures of plastics, wastewater samples will be collected from two distinct types of WWTPs (civil and industrial). The results will provide insight into the practical applications and potential environmental benefits of using natural flocculants instead of synthetic ones, which are currently the most used in treatment plants. This will contribute to the development of more effective strategies for plastic mitigation while also promoting more sustainable treatment processes. To achieve this goal, given that flocculation is one of the final depuration processes in wastewater treatment, it is imperative to also evaluate the effects that flocculants could have on aquatic ecosystems by using the freshwater crustacean Daphnia magna. Specifically, the investigation will span various levels of biological organization, from molecular to organismal. It will assess potential alterations in the proteome, as well as changes in behavior, reproduction, and feeding patterns. This comprehensive approach aims to provide a detailed understanding of how these treatments may influence aquatic organisms and ecosystem health.