Phthalic acid esters (PAEs) are the main additive components of plastics. They can diffuse and migrate during the use and processing of plastics, and they also affect the properties of plastics and pollute the environment. In this study, the comparative molecular similarity index (CoMSIA) was used to construct a three-dimensional quantitative structure-activity relationship (3D-QSAR) model with the valuation index of the volatility of PAEs. Dimethyl phthalate (DMP), an environmental priority pollutant, was selected as a target molecule. The substitution sites and substituent groups in PAE volatilization were determined according to three-dimensional potentiometric map information of the CoMSIA model. Eleven electronegative groups and hydrophilic groups were selected to modify the target molecule through single and double displacement reactions. A total of 55 PAE derivatives were designed, and 19 of those derivatives had an increase in the volatility rating of more than 10%. Based on these derivatives, the environmental friendliness model was used to evaluate the biotoxicity, persistence, and bio-enrichment of PAE derivatives. Seven PAE derivatives with low biotoxicity, persistence, and bio-enrichment were selected. Compared with the plasticizer before modification, DMP derivatives have higher stability and are less likely to volatilize into the environment due to migration and diffusion in plastic products.