Abstract: Chlorophenols (CPs) are characterized as persistent organic pollutants (POPs) and tend to accumulate in aquatic environments, raising significant concerns regarding their aquatic toxicity and ecological risks. At present, there are some deficiencies in the terminal treatment of CP pollutants. For instance, adsorption methods are often costly and may lead to secondary pollution, while ozonation and advanced oxidation processes involve high energy consumption and can exacerbate environmental and ecological harm. Therefore, from the perspective of the pollution source, a certain degree of molecular modification of CPs can effectively solve the problems generated during the terminal treatment. This study aims to reduce the ecological risks of CPs by modifying them at the molecular level and evaluating their environmental safety. A simplified scoring method was employed to assist in the construction of a three-dimensional quantitative structure-activity relationship (3D-QSAR) model for the comprehensive aquatic toxicity effects of CPs. Based on the three-dimensional equipotential diagram of this model, molecular modifications were carried out to design CP derivatives with reduced aquatic toxicity. These newly designed derivative molecules were then subjected to molecular docking with receptor proteins that represent various environmental properties. Docking scores served as indicators to evaluate different environmental and biological effects. As a result, 4 CP derivatives were designed and selected, exhibiting lower aquatic toxicity (reduced by 0.55% to 4.62%), enhanced insecticidal (increased by 5.27% to 30.67%) and anti-corrosion performance (increased by 0.12% to 11.98%), and improved environmental compatibility (enhanced by 16.43% to 18.76%). These derivatives include 2-C₂H₅, 2-CH₂NH₂, 2-NH₂, and 2-SH substituted compounds. Furthermore, molecular dynamics simulations were conducted between the phospholipid bilayer and the CP derivatives to model the adsorption behavior of CPs on cell membranes. The results demonstrated that all four CP derivatives exhibited significantly reduced bioaccumulation effect, with reductions ranging from 9.71% to 40.20%. This study provides a novel approach for assessing the aquatic toxicity and ecological risks of CPs, and offers a theoretical foundation for the development of environmentally friendly modification technologies for CPs. The BRIEF REPORT is available for this paper at http://www.ykcs.ac.cn/en/article/doi/10.15898/j.ykcs.202407190161.