The environmentally friendly modification of chemical pollutants lacks the research of multiple-site simultaneous modification. In addition, there is a lack of efficient screening methods for multiple-sites of molecules, such as polychlorinated biphenyls and their derivatives. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models were established using experimental bioconcentration factor (BCF) data on 58 polychlorinated biphenyls (PCBs). Based on the experimental and predicted values by 3D-QSAR, a 2¹⁰⁻³ fractional factorial design with a resolution of V was used to evaluate the effects of molecular modification (single, double, or triple) at different positions on PCB bioconcentration. Finally, molecular docking technique was used to explore the mechanism of bioconcentration in the receptor of PCBs before and after multiple-site modification. The results showed that ten substitution solutions of main effect, second-order interaction effect and third-order interaction effect that significantly influenced the bioconcentration of dioxin-like PCBs were obtained. Two derivatives prepared by modification of the substituents at two sites were decoupled from the bioconcentration effect. In addition, Molecular docking results showed that the main factors affecting PCB bioconcentration were the degree of matching between hydrophilic/hydrophilic amino acid residues near the binding site and non-covalent forces formed after binding of the ligand to the receptor. The above results explore the rationality of modification schemes for low bioconcentration molecules, and provide theoretical design reference for non-bioconcentration PCBs substitutes.