Background: Vedic Guard is a polyherbal formulation used in the treatment of various ailments, however, is not scientifically assessed for its effect on doxorubicin-induced cardiotoxicity. Objective: To find out the preventive role of Vedic Guard against doxorubicin-induced myocardial toxicity in rats. Materials and Methods: Cardiotoxicity was produced by doxorubicin (15 mg/kg for 2 weeks). Vedic Guard (270 mg/kg, orally) was administered as pre-treatment for 2 weeks and then for 2 weeks alternated with doxorubicin (DXR). The general observations, mortality, histopathology, biomarker like lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate aminotransferase (AST), alanine transaminase (ALT), electrocardiographic (ECG) parameters, antioxidants such as glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were monitored after 3 weeks of last dose. Results: The repeated administration of DXR causes cardiomyopathy associated with an antioxidant deficit. Pre-treatment with Vedic Guard decreases serum enzyme viz LDH, CPK, AST, and ALT levels to that of normal values. Vedic Guard significantly protected the myocardium from the toxic effect of DXR, by increasing the levels of antioxidants such as GSH, SOD, and CAT and decreased the elevated level of malondialdehyde. The study shows significant alteration of ECG pattern in DXR administered rats. The characteristic findings were elevation of ST segment, reduction in P waves, QRS complex, and R-R interval. Vedic Guard showed a protective effect against DXR-induced altered ECG pattern. It also reduced the severity of cellular damage of the myocardium confirmed by histopathology. Conclusion: The results of the present study indicated c ardioprotective effect of Vedic Guard might be attributed to its antioxidant activity.