This study evaluates the cardioprotective effects of a combination of Cleome gynandra (CG) and Barleria gibsonii extract (BG) on rats with isoproterenol (ISO)-induced myocardial necrosis. Significant myocardial necrosis, depletion of the endogenous antioxidants superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), and increases Cardiac markers and serum marker enzymes aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) were observed in ISO-treated rats compared with normal rats. Coadministration of CG & BG at two doses (50 and 75 mg/kg) for 30 days to rats treated with ISO (85 mg/kg, sc) on the 29th and 30th days significantly decreased ISO-induced serum marker enzyme elevations and significantly decreased ISO-elevated myocardial lipid peroxidation marker malondialdehyde (MDA). In the hearts of the treatment groups, a substantial recovery of ISO-depleted activities and levels of CK-MB, AST, LDH, GSH, SOD, and CAT, was observed. The combination of CG 75 mg/kg and BG 100 mg/kg was more protective than the combination of CG 50 mg/kg and BG 100 mg/kg. The oral administration of CG-BG to rodents exposed to ISO demonstrates significant cardiac protection, and restores antioxidant activities. However, the combination did not enhance the cardioprotective activity of either herb when used separately.