BACKGROUND: Myocardial ischemia-reperfusion injury is a pathological phenomenon that occurs after coronary blood flow restoration and poses a threat to patients' lives. Its mechanisms are closely related to oxidative stress and mitochondrial dysfunction. Yellow Wine Polyphenolic Compounds, a dietary polyphenol with significant antioxidant effects, have been shown to offer protection in various cardiovascular diseases. However, their role in MIRI remains under-researched. METHODS: In vivo experiments, TTC staining was used to assess myocardial viability, and cardiac ultrasound was employed to measure left ventricular ejection function. Morphological staining and detection of myocardial injury markers were used to evaluate cardiac damage. Transmission electron microscopy was used to observe mitochondrial morphology in myocardial tissue, and ELISA was performed to evaluate the activity of mitochondrial complexes. Adeno-associated virus knockdown was utilized to verify the role of Nrf2. In in vitro experiments, confocal microscopy was used to scan mitochondrial morphology in cardiomyocytes and to observe the intracellular localization of the Nrf2 molecule. RESULTS: TTC staining showed that MIRI significantly increased the infarct size in the left ventricle, whereas pre-treatment with YWPC (Yellow Wine Polyphenol Compound) significantly reduced the infarct area. Cardiac ultrasound demonstrated that YWPC intervention preserved left ventricular ejection fraction. Morphological staining and detection of myocardial injury markers revealed that MIRI caused tissue edema, increased myocardial apoptosis and damage, but YWPC pre-treatment alleviated these injuries. Transmission electron microscopy showed that YWPC reversed the excessive mitochondrial fission caused by MIRI. Immunofluorescence indicated that YWPC significantly promoted Nrf2 nuclear translocation and increased the expression of downstream antioxidant molecules. CONCLUSION: YWPC pre-treatment can protect myocardial tissue by reducing the excessive mitochondrial fission induced by MIRI, and Nrf2 mediates these effects.