Commiphora mukul commonly known as Guggul is one of the oldest and commonly consumed herb for promoting heart and vascular health. Present study was undertaken to evaluate cardioprotective potential of Commiphora mukul against isoprenaline-induced myocardial necrosis in rats. Wistar albino rats were divided into three main groups: sham (saline only), isoprenaline control (saline and isoprenaline) and Commiphora mukul treated (Commiphora mukul and isoprenaline) groups. Commiphora mukul was administered in three doses 100, 200 and 400 mg kg(-1) p.o. for 30 days. On 29th and 30th day, the animals of isoprenaline control and Commiphora mukulpretreatment groups were administered isoprenaline (85 mg kg(-1); s.c.), consecutively at an interval of 24 hr. Isoprenaline administration produced a significant (p < 0.05) decrease in myocardial antioxidants; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), reduced glutathione (GSH), and myocyte injury marker enzymes creatine-phosphokinase-MB (CK-MB) and lactate dehydrogenase (LDH) along with enhanced lipid peroxidation; malondialdehyde (MDA) in heart. Commiphora mukul pretreatment reversed the isoprenaline-induced oxidative changes in rat myocardium by significant (p < 0.05) increase in SOD, CAT, GSHPx, GSH and reduction of MDA. In addition to improving myocardial antioxidant status, Commiphora mukul also prevented the leakage of LDH and CK-MB from heart. Further, histopathological examination showed the reduction of necrosis, edema and inflammation following Commiphora mukul pretreatment. Based on present findings, it is concluded that Commiphora mukul may be a potential preventive and therapeutic agent against the oxidative stress associated ischemic heart disease owing to antioxidant and antiperoxidative activity.