Objectives: Scutellarin, which is obtained from Erigeron breviscapus Hand-Mazz (EBHM), is a flavonoid that has demonstrated the ability to safeguard neural stem cells from hypoxia-induced damage and prevent cell apoptosis. The aim of this study was to investigate the beneficial impacts of Scutellarin on mitophagy in both in vivo and in vitro models of myocardial ischemiareperfusion (I/R) injury. Materials and Methods: Prior to inducing models of myocardial I/R injury, mice were administered either Scutellarin (50 mg/kg/day) or a vehicle for seven consecutive days. The mice underwent I/R injury (30 min of left anterior descending (LAD) coronary artery ligation followed by 120 min of reperfusion). Myocardial injury markers were assessed by the enzyme-linked immunosorbent assay (ELISA). The size of the myocardial infarction was measured via 2,3,5-triphenyl tetrazolium chloride triazole staining, and the protein expression of LC3 and caspase-3 was determined through Western blot analysis. In vitro experiments were conducted utilizing cultured H9C2 cells subjected to an oxygen-glucose deprivation/reoxygenation model to investigate the underlying mechanism(s) of Scutellarin's positive effects (50 mu M). Results: It shows that Scutellarin treatment reduced the size of the myocardial infarctions and decreased the levels of myocardial injury markers. Western blot analysis showed that protein expression of caspase-3 was decreasing and the ratio of LC3. to LC3. was increasing in the Scutellarin group. In vitro, Scutellarin decreased oxidative stress markers, stabilized mitochondrial membrane potential (Delta Psi m), decreased mitochondrial permeability transition pore (mPTP) opening rate, promoted mitochondrial fusion, inhibited mitochondrial fission, and increased adenosine triphosphate (ATP) production and cell viability. Scutellarin increased the commitment of mitophagy by regulating Pink and Parkin, while apoptosis decreased. cAMP-response element-binding protein (CREB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation were also modulated by Scutellarin. Conclusion: The myocardial protective effect of Scutellarin may be associated with the phosphorylation of CREB and ERK1/2.