BACKGROUND AND OBJECTIVE: Myocardial ischemia-reperfusion (I/R) injury remains a significant challenge in the treatment of acute myocardial infarction, highlighting the urgent need for effective cardioprotective strategies. Sevoflurane (Sev), a widely used anesthetic, has demonstrated notable cardioprotective potential. This study investigated whether Sev mitigates ferroptosis in myocardial cells by inhibiting the USP7-mediated PTEN/PI3K/AKT pathway. METHODS: Rat myocardial I/R injury and H9c2 cell hypoxia/reoxygenation (H/R) injury models were established. Myocardial injury was assessed through cTnT levels, hemodynamic parameters, and histological analyses. Cell viability, LDH release, TUNEL staining, and ferroptosis markers (GSH, MDA, Fe²(+), ROS) were evaluated. Co-IP and CHX assays were employed to explore USP7's regulation of PTEN stability. RESULTS: Sev significantly reduced serum cTnT levels, improved hemodynamic function, decreased infarct size, and alleviated myocardial fibrosis and inflammation in rats subjected to I/R injury. In H9c2 cells, Sev enhanced cell viability and suppressed apoptosis. Sev reversed hypoxia/reoxygenation (H/R)-induced USP7 overexpression and ferroptosis, whereas USP7 overexpression attenuated Sev's protective effects. CONCLUSION: Sev protected against myocardial I/R injury by inhibiting USP7, destabilizing PTEN, activating the PI3K/AKT pathway, and suppressing ferroptosis. These findings elucidated the molecular mechanism of Sev's cardioprotective effect and suggested USP7 as a potential therapeutic target for myocardial protection.