Liver transplantation is currently recognized as the only effective therapeutic option for end-stage liver disease. Hepatic ischemia-reperfusion injury (IRI) remains a major cause of graft damage or dysfunction, and is mediated by the abundant production of reactive oxygen species (ROS) and a complex cascade of inflammation during the reperfusion period. However, no universal antioxidant has been applied in clinical practice due to its low bioavailability and non-specific targeting. Herein, cerium oxide and manganese oxide nanocomposites (CM NCs), with the advantages of high biocompatibility, passive liver-targeting and short-term metabolic excretion, were synthesized as a nanodrug for hepatic IRI therapy. The CM NCs exhibited excellent superoxide dismutase (SOD) and catalase (CAT) mimetic activity to scavenge ROS and generate oxygen (O2). Therefore, CM NCs could alleviate oxidative stress, subsequently suppress the activation of Kupffer cells (KCs) and neutrophils, and reduce the secretion of inflammatory factors due to the synergistic effect of ROS scavenging and O2 production. By exploring the underlying mechanisms of the CM NCs in the treatment of hepatic IRI, we suggest that the CM NCs with ROS scavenging and inflammation regulation capacity show clinical potential for hepatic IRI management and provide new perspectives in the treatment of other oxidative-stress-related diseases.