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Objective: To investigate the cardioprotective effect of Yiqi Huoxue granule (YQHXG) in the regulation of autophagy in rats induced with myocardial infarction (MI). Methods: An acute MI animal model was established by ligation of the left anterior descending branch of the coronary artery in Sprague-Dawley rats. Besides, 20 rats received sham operation were classified into a control group. The remaining 59 rats were randomly divided into MI model group (n = 19), YQHXG group (n=20), and perindopril group (n=20). Relevant indicators on days 7 and 28 were observed in each group. Left ventricular function was determined by echocardiography. The structure and morphology of mitochondria, and the number of autophagic vesicles, were observed by transmission electron microscopy. The mRNA and protein expression levels of LC3, FUNDC1, Beclin-1, and BNIP3 were examined in the tissue of the MI marginal area. Results: Compared with the MI model group, YQHXG showed obvious improvements in cardiac func-tions. Observing the microscopic morphology of the heart tissue, myocardial tissue damage attenuated, autophagic signs of autophagosomes and autolysosomes reduced, vacuolization in mitochondria miti-gated, and mitochondria arranged in order. YQHXG could reduce the degree of tissue lesion after MI and regulate the expression of autophagy-related molecules at different stages. On Day 7, YQHXG signifi-cantly downregulated the expression of Fundc1, Becn1, Bnip3 mRNA and reduced the levels of FUNDC1, Beclin-1, BNIP3, and LC3 B proteins expression (all P < .001). On Day 28, YQHXG could upregulate the expression of Becn1, Fundc1 and Bnip3 mRNA and increased the levels of the corresponding proteins expression (all P<.001). Besides, it also increased LC3 B protein expression level (P=.0344). Conclusion: YQHXG regulated the expression of mitochondrial autophagy-related factors in myocardial tissue and mitochondrial autophagic activity at different stages to protect the heart following MI.