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Myocardial ischemia-reperfusion injury (MIRI) causes severe clinical complications in patients. Although gemfibrozil (GEM) has been extensively studied in metabolic diseases, its effects on MIRI remain unknown. In this study, we investigated the pharmacological effects and molecular mechanisms of GEM in alleviating MIRI through adenosine 5'-monophosphate-activated protein kinase (AMPK) modulation. The results showed that pre-administration of GEM (100 mg/kg) provided significant protection against MIRI in mice, as indicated by reduced infarct size, lower cardiac injury markers such as hydrogen peroxide (H₂O₂), lactate dehydrogenase (LDH), and creatine kinase (CK), and improved cardiac function. This cardioprotective effect of GEM was associated with enhanced myocardial antioxidant capacity, as shown by decreased dihydroethidium (DHE) fluorescence density and reduced nitric oxide (NO) and malondialdehyde (MDA) levels in ischemic cardiac tissue. GEM pretreatment also prevented the I/R-induced increase in TUNEL-positive cells and expression of caspase-3, caspase-9, and Bax, as well as the I/R-induced decrease in Bcl-2 expression in ischemic cardiac tissue, indicating an anti-apoptotic effect of GEM in MIRI. In addition, GEM pretreatment prevented the I/R-induced increase in mRNA expression levels of tumour necrosis factor-α (Tnf-α), interleukin-β (Il-1β), and Il-6 in ischemic cardiac tissue. Further analysis showed that GEM administration prevented the I/R-induced decrease in phospho-AMPK levels in ischemic cardiac tissue, and pharmacological inhibition of AMPK with dorsomorphin (DSMF) abolished all cardioprotective effects of GEM. Taken together, these results suggest that GEM mitigates MIRI-induced cardiac injury by inhibiting apoptosis and oxidative stress via modulation of AMPK, supporting its potential for reducing MIRI-related cardiac damage.