Objective To investigate the protective effect of icaritin liposme against hepatic ischemia /reperfusion (I/R) injury in rats and its mechanisms. Methods A total of 120 male SD rats were randomly divided into four groups: icaritin liposome+I/R (ICT+I/R) group, vechicle liposome+I/R (LIP+I/R) group, I/R group and sham operation (Sham) group. Each group was randomly divided into two subgroups of 2 h and 6 h. The rats in the Sham group were only with free hilum, and the other three groups were subjected to 70% liver ischemia for 60 min. Icaritin liposome (1.5 mg/kg) or vechile lipsome (with same volume of icaritin liposome) were intraportal venously injected in the ICT+I/R and LIP+I/R groups at 10 min before ischemia, without any pretreatment in the I/R group. Blood and liver tissue samples in each group were obtained at 2 h and 6 h after reperfusion to measure the levels of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), and the contents of superoxide dismutase (SOD), malondialdehyd (MDA), nitric oxide (NO), nitric oxide synthase (NOS), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and myeloperoxidase (MPO) in liver tissues. The morphology of liver tissues was observed by H-E staining. The apoptosis of liver cells and apoptosis index (AI) were calculated by TUNEL staining. Results Compared with the LIP+I/R and IR groups, ALT level, MDA and MPO contents, and AI were significantly decreased in the ICT+I/R group at 2 h after reperfusion (P<0.05, P<0.01). At 6 h after reperfusion, the ALT and AST levels, MDA content, and AI in the ICT+I/R group were significantly reduced, and the contents of SOD, NO, NOS, and eNOS were significantly increased compared with the LIP+I/R and IR groups (P<0.05, P<0.01). Conclusion Icaritin liposome can reduce liver I/R injury by increasing the contents of SOD and NO, reducing the formation of MDA, promoting the expression of eNOS, and inhibiting the accumulation of MPO and liver cell apoptosis.