A series of environment-friendly plasticizers has been synthesized from castor oil through a mild esterification/epoxidation reaction. The modified epoxy acetylated castor oil (EACO) can plastify poly(vinyl chloride) (PVC) efficiently, even better than the commercial plasticizers dioctyl terephthalate (DOTP) and epoxidized soybean oil (ESO), in terms of in tensile strength, migration stability, solvent extraction stability and thermal stability. Specifically, the tensile strength and elongation at break of a PVC sample plastified by epoxy acetylated castor oil (EACO) were 18.5 and 10.0% higher than that of DOTP, and 13.9 and 23.8% higher than that of ESO, respectively. Volatility, migration, solvent extraction and thermal stability tests indicated that the presence of carbon–carbon double bonds and hydroxy groups reduce the compatibility of a plasticizer with PVC while the presence of epoxy groups and ester bonds can improve the plasticizing effect of the plasticizer on PVC. In addition, alkyl groups can improve the plasticizing effect on PVC while benzene rings increase the rigidity of the PVC. The design strategy based on castor oil highlights a sustainable avenue for preparing cost-effective and high-efficiency plasticizers.