Sesamol, an active component of sesame oil exhibits wide array of biological properties. The present was carried out to scrutinize the protective role of sesamol in myocardial ischemia reperfusion (M I/R) oxidative cardiac injury in a murine model. Pretreatment of Sesamol (50 mg/kg) was done for 7 days before the surgery period. M I/R injury were surgically induced by left anterior descending (LAD) ligation for 45 min followed by 3 h of reperfusion. The cardioprotective efficacy of sesamol was authenticated by measuring biochemical markers, protein expression of apoptotic related genes and inflammatory gene expression. In the present study, M I/R rats displayed elevated infarct size, serum cardiac markers (CK, LDH and cTnI) MDA and MPO activity. Meanwhile, the level of antioxidants (SOD, CAT and GSH) was significantly reduced in ischemic tissues due to oxidative stress. Further, serum (TNF-α, IL-1β) and mRNA (TNF-α, IL-1β and NF-?B) level of inflammatory mediators were significantly elevated M I/R rats. Protein expression of apoptotic related genes (Bcl-2, Bax and Caspase-3) were significantly altered in the event of M I/R injury. However, sesamol treatment significantly reduced the infarct size, resorted the cardiac markers, reduced the lipid peroxidation, neutrophil infiltration and increased the antioxidants level. Furthermore, sesamol administration elicited significant downregulation of inflammatory genes, Bax, Caspase-3 apoptotic proteins and upregulation of anti-apoptotic Bcl-2 protein. In conclusion, our study demonstrated that sesamol exerts cardioprotective property against M I/R injury mediated through antioxidant, anti-inflammatory and anti-apoptotic mechanism.