The objective of the study aims to evaluate the combined protective effects of coenzyme Q10 and magnesium sulphate on isoproterenol induced myocardial damage in rats. CoenzymeQ10 (50 mg/kg) and magnesium sulphate (10 mg/kg) were administered orally to wistar rats in individual or in combination for 30 days.  At the end of this period, rats were administered isoproterenol (85 mg/kg i.p.) intraperitonially for two consecutive days to induce myocardial injury. After induction, rats were anaesthetized and plasma was collected to analyze various biochemical parameters. Further, immunohistochemistry and histopathology of the heart tissue was performed. Induction of rats with isoproterenol resulted in a marked (p<0.001) elevation of infarct size , level of serum marker enzymes (AST, ALT, LDH and CK- MB), lipid peroxidation , protein expression of alpha- smooth muscle actin (α SMA)  along with alterations in histopathology. Pretreatment with combination of coenzyme Q10 (CoQ10) and magnesium sulphate (MgSO4) exhibited a significant (p<0.001) decrease in serum marker enzyme, infarct size , lipid peroxidation , protein expression of α- smooth muscle actin (α-SMA) and showed preservation of cardiomyocytes histo-architecture when compared with individual treated  groups. This study demonstrated the synergistic cardio protective effect of coenzymeQ10 (CoQ10) and magnesium Sulphate (MgSO₄) in isoproterenol induced myocardial damage in rats demonstrated that the oral pre-treatment with CoQ10 and Magnesium sulphate were associated with moderate protection against ISO-induced cardio toxicity and cardiac hypertrophy. The mechanism might be associated with the enhancement of antioxidant defense system. The present results can form the basis that combination of CoQ10 and magnesium sulphate proved to be a potential therapeutic agent for pharmacological management of ischemic heart disease. It could provide experimental evidence to support the rationality of combinatorial use in the prevention of the onset and progression of myocardial injury.