The continuous increase in the production and use of plastics and their consequent release into natural ecosystems represent a significant concern for both human and environmental health. Wastewater Treatment Plants (WWTPs) have been identified as one of the major pathways for plastics entering aquatic environments. Although several studies have demonstrated the effectiveness of coagulants/flocculants in plastic removal in laboratory tests, their practical application in WWTPs remains largely unexplored. This study evaluated the effectiveness of different commercial polymer-based flocculants, both synthetic and natural, in reducing plastic concentrations in wastewaters. Jar tests were performed using these wastewaters adding four commercial flocculants (2 bio-based and 2 polyacrylamide-based) at three concentrations close to the dosage recommended for suspended solids’ removal (0.10 g/L), in combination with different plastic mixtures artificially created. Plastic removal efficiency was quantified by comparing the number of particles remaining in suspension after treatment with the initial amount. In addition, many chemical parameters were monitored to assess regulatory compliance (European Directive (EU) 2024/3019). The results demonstrated that the use of coagulants, chemical agents that promote particles aggregation, was necessary to reach the chemical requirements of the Directive. Poly-aluminum chloride (PAC) administered at 0.08 g/L showed the best performance compared to other coagulants, while complying with the limits imposed by the EU Directive. The various flocculation tests, with the addition of this necessary PAC concentration, showed similar plastic removal efficiencies, with percentages of 96.25% ± 0.72 for bio-based polymers and 99.58% ± 1.65 for polyacrylamide-based polymers. These findings suggest the applicability of flocculation-based treatments for plastic mitigation in industrial WWTPs and suggest that natural flocculants may offer a sustainable alternative to synthetic polymers, improving environmental safety of wastewater treatment processes.