The present study was done to evaluate the role of grape seed proanthocyanidins (GSPs) in isoproterenol (ISO)-induced myocardial injury in rats. Male albino Wistar rats were pretreated with GSP (50, 100, and 150 mg/kg), 6 days a week, for 5 weeks. Induction of rats with ISO (85 mg/kg body weight, intraperitoneally) for 2 days resulted in a significant elevation of thiobarbituric acid-reactive substances in serum, mitochondrial cholesterol, triglycerides, and free fatty acids. A significant decrease was observed in serum reduced glutathione; ascorbic acid; α-tocopherol; ceruloplasmin; and mitochondrial cytochromes (b, c, c1, and aa3), phospholipids, and adenosine triphosphate. Pretreatment with GSP (100 and 150 mg/kg) positively altered the levels of all the parameters studied and restored normal mitochondrial function when compared with ISO-induced rats. The effect at a dose of 50 mg/kg was not promising when compared with the other 2 doses (100 and 150 mg/kg). These results confirm the efficacy of GSP in alleviating ISO-induced myocardial injury.