Liver transplantation, the only curative option for end-stage liver disease, is limited by ischemia-reperfusion injury, with hepatocyte ferroptosis as a key pathogenic mechanism. CD36, a fatty acid translocase, drives the progression of multiple liver diseases. Yet, its role in hepatic ischemia-reperfusion injury (HIRI) and ferroptosis remains unclear. In this study, we generated full and hepatocyte-specific CD36 knockout mice to investigate its impact on HIRI. A significant upregulation of CD36 was observed in livers following ischemia-reperfusion (I/R) injury and in primary hepatocytes after hypoxia-reoxygenation (H/R). CD36 knockout alleviated liver injury and ferroptosis in HIRI models. In vitro, CD36 silencing suppressed H/R induced ferroptosis. Furthermore, our results establish rutin, a flavonoid derived from Gardenia, as a novel inhibitor of hepatocyte CD36 that alleviates HIRI. Mechanistically, CD36 regulates fatty acid binding protein 5 (FABP5) to reprogram lipid metabolism and drive ferroptosis in HIRI. Additionally, Rutin suppresses CD36 transcription through the stabilization of hepatocyte nuclear factor 4 α (HNF4α). Our findings demonstrate that CD36 exacerbates HIRI by regulating FABP5-mediated lipid metabolism and ferroptosis, while rutin exerts protective effects via CD36 inhibition. These results highlight the therapeutic potential of rutin for HIRI and identify the CD36/FABP5 axis as a novel target for intervention.