Introduction Bisphenol-A (BPA), an estrogenic compound, is used in the manufacture of polycarbonate plastics and epoxy resins. Sesame oil (SO) is a potent antioxidant dietary source for human health. Aim The present study was conducted to estimate the protective effects of SO against BPA-induced cardiotoxicity. Materials and methods Thirty two adult rats were divided into 4 equal groups eight rat for each; Control group, 2 Treated group, one group received BPA (25 mg/kg b wt) orally 5 times/ weak for 4 weeks and other group rats received (50 mg/kg b. wt) orally 5 times /weak for 4 weeks. Protected group received sesame oil orally at a dose 10 mL/kg b wt orally daily for 4 weeks to the rat group which received the high dose of BPA. After the end of treatments, the heart of each killed animal was subjected to histopathological examination by hematoxylin and eosin, Masson’s, and NOS stain. In addition, blood was collected for biochemical assessment of the enzymes. Results Administration of high-dose BPA (50 mg/kg b. wt) significantly increased the weight of rats. Several histopathological alterations in cardiac tissue and elevation in malondialdehyde, creatine phosphokinase-MB, and glutathione-S-transferase activity and reduction of glutathione and catalase occurred when compared with the control. Low-dose BPA (25 mg/kg b. wt) produced mild histopathological effect on the heart. On the contrary, oral gavages of SO with BPA was effective in the reduction of weight, amelioration of histopathological alterations, and in the reduction of the malondialdehyde, creatine phosphokinase-MB, and glutathioneS-transferase activity levels and elevation of glutathione and catalase activity when compared with high-dose BPA-treated rats. Conclusion The present study provided clear evidence that SO possesses a promising protective activity against the cardiotoxic effects of BPA