<p>The present investigation is aiming to explore the cardioprotective implications of Graphene-based Fe₂O₃ nanozymes and Fe₂O₃ nanoparticles against isoproterenol (ISO)-instigated myocardial infarction (MI) in rats. Fe₂O₃ nanoparticles were prepared through green synthesis method using the plant extract of <i>Trigonella foenum-graecum</i>, and graphene was synthesized by the modified hammer method. However, Fe₂O₃-graphene nanozymes were fabricated using ultrasonication method. Oxidative stress, cardiac injury and inflammation were assessed via biochemical markers including cardiac indicators (Troponin I, creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH)), antioxidative assembly (superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT)), inflammatory markers (IL-1β, IL-6 and TNF-α), apoptotic related proteins (BaX and Bcl-2) lipid profile, hematological and hepatological parameters. Histopathological changes in myocardium were assessed via hematoxylin and eosin (H&amp;E) staining. Graphene-based Fe₂O₃ nanozymes significantly cast a restorative influence on ISO-induced cardiac damage by enhancing the levels of SOD (<i>p</i> &lt; 0.01 **), GSH (<i>p</i> &lt; 0.01 **) and CAT enzymes accompanied by significant reduction in levels of cardiac biomarkers (LDH, CK-MB and Troponin I) and lipid content in blood serum (<i>p</i> &lt; 0.001 ***). Likewise, normal restoration level of hematological, inflammatory and molecular markers was also observed with significance level of (<i>p</i> &lt; 0.001 ***). Histological observations confirmed reduced myocardial damage and inflammation in the treated group. As compared to the Fe₂O₃ nanoparticles, graphene-based Fe₂O₃ nanozymes exhibited greater protective efficacy, highlighting their potential in mitigating ISO-induced oxidative stress and inflammation. These findings suggest that graphene-based Fe₂O₃ nanozymes are promising candidates for cardio protection in myocardial injury models.</p> Graphical Abstract <p></p>