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Autophagy is critical for myocardial ischemia-reperfusion (I/R) injury. However, there is still considerable debate over its protective and deleterious effects. The purpose of this study was to determine the involvement of the proprotein convertase subtilisin/Kexin type 9 (PCSK9) and its inhibitor in myocardial ischemia-reperfusion injury autophagy (MRI). Nine groups of eighty rats were used: sham, I/R2 h, I/R4 h, I/R6 h, I/R8 h, I/R1 d, and I/R2 d. A 30-min coronary artery blockage was used to produce myocardial IR. The time required for reperfusion rose linearly with the time gradient, from 2 h to 2 days. Following the determination of the best reperfusion period, three groups were formed: sham, I/R, and I/R + P (PCSK9 inhibitor (evolocumab) 10 mg/kg diluted in 2 ml sterile injection water was administered subcutaneously 1 week and half an hour before to surgery. Each group's infarction area was determined by electrocardiography (ECG), cardiac function, and 2,3,5-triphenyltetrazolium chloride (TTC) /Evan Blue (EB) staining. To detect morphological alterations in myocardial cells in each group, hematoxylin and eosin (HE) staining was used. Meanwhile, western blotting, immunohistochemistry, and Masson trichrome staining were utilized to quantify myocardial fibrosis and PCSK9 and autophagy protein expression. The results indicated that PCSK9 expression levels increased significantly in MRI, as indicated by increased levels of the autophagy regulatory protein light chain 3 (LC3) and Beclin-1, which activated autophagy in cardiomyocytes, exacerbated myocardial injury, and increased the size of myocardial infarcts. Meanwhile, PCSK9 regulates mitophagy via the Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3) pathway, which controls myocardial infarction MRI throughout. Additionally, the PCSK9 inhibitor significantly decreased autophagy, enhanced cardiac function, and reduced the extent of reperfusion injury, consequently reducing myocardial infarct size expansion. PCSK9 is upregulated in the myocardial ischemia-reperfusion injury hearts and regulates mitophagy via the BNIP3 pathway, which in turn contributes to reperfusion injury after myocardial infarction. PCSK9 inhibition protects against myocardial ischemia-reperfusion injury via suppressing autophagy. • the expression levels of PCSK9 and autophagy markers rose in a proportional ratio with increasing reperfusion time, peaking at 1 day of reperfusion and thereafter decreased. Meanwhile, we believe that PCSK9 regulation of mitophagy peaked at 1 day after reperfusion, boosting autophagosome formation, intensifying mitochondrial damage, and exacerbating reperfusion injury development. (2) In response to MRI, we discovered a gradual rise in PCSK9 in reperfused hearts, which contributes to scar growth and cardiac dysfunction. • Data demonstrated that elevated PCSK9 expression hastened the progression of myocardial infarction by triggering mitochondrial apoptosis in cardiomyocytes after passing through the BNIP3 pathway. It causes more severe reperfusion injury, which increases the extent of the myocardial infarction. • Pretreatment with PCSK9 inhibitors reduced PCSK9 expression, slowed autophagy formation, and reduced myocardial ischemia-reperfusion injury, enhancing ventricular remodeling and improve cardiac function, resulting in a smaller myocardial infarction. • We believe PCSK9 has a role in the evolution of myocardial infarction, and ischemia-reperfusion damage. • PCSK9 is up-regulated in the hearts with myocardial ischemia-reperfusion injury and regulates mitophagy through the BNIP3 pathway, thus promoting reperfusion injury after myocardial infarction. PCSK9 inhibition protects against myocardial ischemia-reperfusion injury via suppressing autophagy. [ABSTRACT FROM AUTHOR]