It is known that chewing Betel quid with tobacco (BQT) or without tobacco (BQ) is a major etiological factor for cardiovascular complications and calcium channel blockers (CCBs) are the major class of drugs prescribed widely for myocardial disturbances. The possible pharmacodynamic interaction between CCBs (verapamil, amlodipine and diltiazem) and BQ/BQT was studied on isoproterenol (ISO)-induced myocardial necrosis in mice. Influence of (CCBs) therapy on pretreated animals at times of myocardial stress were determined by estimating diagnostic marker enzymes such as lactate dehydrogenase (LDH) and creatine phosphokinase isoenzyme (CK-MB) in serum and heart tissue homogenate (HTH). Administration of CCBs to mice pretreated with BQ produced a significant decrease and increase in biomarker enzyme levels in serum and HTH respectively. Further, incorporation of diltiazem and amlodipine in BQT pretreated mice significantly elevated enzyme levels in HTH, whereas, amlodipine administration during BQT treatment showed significant fall in enzyme levels in serum. The results indicated that BQT is cardiotoxic and its effect cannot be reversed using CCBs while BQ is cardioprotective, whose activity was further augmented by amlodipine. Histopathological studies confirmed the biochemical findings.