Polyethylene terephthalate (PET) microplastics constitute a significant portion of plastic pollution in the environment and pose substantial environmental challenges. In this study, the effectiveness of the Fenton process and post-oxidation coagulation for the removal of non-weathered and UV-weathered PET microplastics (PET MPs) were investigated. A response surface methodology was used to investigate the interplay between PET concentration and ferrous ion (Fe2+) concentration. The models revealed an intricate interplay between these variables, highlighting the need for a balanced system for optimal PET MP removal. For non-weathered PET, the simultaneous increase in the concentrations of both PET microplastics and Fe2+ was found to enhance the removal efficiency. However, this synergistic effect was not observed in UV-weathered PET, which also demonstrated a more pronounced effect from the Fe2+ concentration. The statistical analysis provided a strong basis for the validity of the models. X-ray photoemission spectroscopy (XPS) further elucidated the mechanisms behind these findings, revealing that UV weathering results in surface changes, which facilitate hydroxyl radical oxidation. These findings underline the complexity of the Fenton process in PET microplastic removal and the different behavior of non-weathered and UV-weathered microplastics. This has significant implications for tailoring remediation strategies and underscores the importance of considering environmental weathering in these strategies.