The present study was designed to evaluate the cardioprotective potential of hydro-alcoholic extract of Withania somnifera on the basis of haemodynamic, histopathological and biochemical parameters in the isoprenaline-(isoproterenol) induced myocardial necrosis in rats and to compare with Vitamin E, a known cardioprotective antioxidant. Wistar albino male rats (150-200 g) were divided into six main groups: sham, isoprenaline control, Withania somnifera/Vitamin E control and Withania somnifera/Vitamin E treatment groups. Withania somnifera was administered at doses 25, 50 and 100 mg/kg and Vitamin E at a dose of 100 mg/kg, orally for 4 weeks. On days 29 and 30, the rats in the isoprenaline control and Withania somnifera/Vitamin E treatment groups were given isoprenaline (85 mg/kg), subcutaneously at an interval of 24 hr. On day 31, haemodynamic parameters were recorded and the hearts were subsequently removed and processed for histopathological and biochemical studies. A significant decrease in glutathione (P<0.05), activities of superoxide dismutase, catalase, creatinine phosphokinase and lactate dehydrogenase (P<0.01) as well as increase in lipid peroxidation marker malonyldialdehyde level (P<0.01) was observed in the hearts of isoproterenol control group rats as compared to sham control. However, we have not observed any significant changes in activity of glutathione peroxidase and protein levels. Left ventricular dysfunction was seen as a decrease in heart rate, left ventricular rate of peak positive and negative pressure change and elevated left ventricular end-diastolic pressure in the control group was recorded. On histopathological examination, myocardial damage was further confirmed. Our data show that Withania somnifera (25, 50 and 100 mg/kg) exerts a strong cardioprotective effect in the experimental model of isoprenaline-induced myonecrosis in rats. Augmentation of endogenous antioxidants, maintenance of the myocardial antioxidant status and significant restoration of most of the altered haemodynamic parameters may contribute to its cardioprotective effect. Among the different doses studied, Withania somnifera at 50 mg/kg dose produced maximum cardioprotective effect.