Hepatic ischemia-reperfusion injury (HIRI), a major complication in liver surgery and transplantation, is characterized by oxidative stress and an increased inflammatory response. Unfortunately, current strategies for the prevention or treatment of HIRI are limited. This study presents CMM, an innovative nanotherapeutic platform that integrates melatonin (Me) within cerium-based metal-organic frameworks (Ce-MOFs). CMM demonstrated outstanding biocompatibility, liver accumulation, catalase and superoxide dismutase activities, along with inflammation regulation. CMM significantly reduced reactive oxygen species (ROS) generation, preserved mitochondrial function, inhibited the BAX/BCL-2 apoptotic pathway, and protected hepatocytes. Furthermore, CMM reprogrammed pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages by suppressing NF-κB pathway activation, which significantly decreased the secretion of inflammatory cytokines such as TNF-α, IL-1β, and IL-6. In the HIRI mouse model, CMM demonstrated robust hepatocyte protection and inhibition of inflammation. Additionally, RNA-seq analysis revealed that CMM modulated key inflammatory and antioxidant pathways, including cytokine signaling and glutathione metabolism. These findings underscore the potential of CMM to interrupt the oxidative stress-inflammation feedback loop, indicating its promise as an innovative treatment for HIRI.