Background: The Nrf2/HO-1 signaling pathway is a critical antioxidative stress and cytoprotective pathway, and oxidative stress plays a significant role in myocardial ischemia-reperfusion injury (MIRI). Liquiritigenin, a flavonoid compound derived from licorice, is hypothesized to alleviate MIRI, though its specific mechanism remains unclear. Methods: Following a 15-min pretreatment with liquiritigenin, animals underwent myocardial ischemia-reperfusion injury induction comprising 30-min coronary occlusion and 2-h reperfusion. Continuous cardiac monitoring incorporated both electrocardiography (ECG) and ventricular pressure dynamics, specifically tracking systolic pressure (LVSP), end-diastolic pressure (LVEDP), and ventricular contractility indices (±dp/dtmax). Post-experimental biospecimen analysis included: Myocardial injury evaluation: Serum quantification of lactate dehydrogenase and CK-MB isoenzyme levels. Redox status assessment: Measurement of antioxidant enzyme activities (SOD, GSH) and lipid peroxidation biomarker MDA concentration Histopathological damage: Evaluated via hematoxylin-eosin (HE) staining. Apoptosis: Detected by TUNEL assay. Protein expression: Western blot analysis of Nrf2/HO-1 pathway components (Nrf2, Keap1, HO-1). Conclusion: Liquiritigenin exerts cardioprotective effects against MIRI by activating the Nrf2/HO-1 signaling pathway, thereby attenuating post-reperfusion oxidative stress. This study elucidates the central role of Nrf2/HO-1 pathway interactions in MIRI and identifies liquiritigenin as a potential therapeutic candidate for targeting this pathway.