The purpose of this study was to evaluate the protective role of soursop leaves and avocado seed extract, single or in combination against isoproterenol (ISO)-induced myocardial infarction (MI) in Male Wistar rats. The extracts were given orally for 15 days, while ISO 85 mg/kg were administered intraperitoneally twice at an interval 24h. The measured parameters were serum levels of biomarkers of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), and creatine kinase-MB (CK-MB). Furthermore, histopathology was done to observe the integrity of the myocardial cell membrane. The results showed that pretreatment of single extract of soursop leaves (150 mg/kg) and avocado seeds (150 mg/kg) did not significantly inhibit the effects of ISO on ALT, AST, LDH, CK, and CK-MB. Meanwhile, pretreatment of the combination of soursop leaf ethanol extract and avocado seeds 75-75 mg/kg b.w. inhibited the increase of ALT, AST, LDH, CK, and CK-MB biomarkers level (5.4%; 27.08%; 35.68%; 14.29%; and 43.79%, respectively) significantly as compared to the ISO control group. The combination extract at doses of 75 mg/kg b.w. each could maintain the integrity of the myocardial cell membrane upon ISO administration. Overall, the cardioprotective activity of this extract combination of soursop leaf ethanol extract and avocado seeds at a dose of 75 mg/kg each was synergistic.