Myocardial ischemia-reperfusion (I/R) injury is a critical complication following reperfusion therapy for myocardial infarction. As a marker of I/R injury, apoptosis plays an important role in myocardial ischemia-reperfusion injury. Programmed Cell Death 4 (PDCD4) regulates apoptosis in MI/RI, but the mechanism is not yet fully elucidated. In this study, we demonstrate that PDCD4 expression was significantly upregulated in a myocardial I/R injury model. Genetic deletion of PDCD4 markedly reduced infarct size, serum biomarkers of injury (CK-MB, cTnT, LDH), and apoptosis in vivo. Mechanistically, PDCD4 directly interacts with AKT, inhibiting its phosphorylation by reducing ubiquitination. This suppression of AKT activity decreased BCL-2 levels, promoting mitochondrial apoptosis. Silencing PDCD4 restored AKT phosphorylation, attenuated apoptosis, and alleviated myocardial damage. Our findings establish PDCD4 as a key driver of myocardial I/R injury via AKT-mediated apoptosis and highlight its therapeutic potential.