Liver transplantation has been a routine treatment for the end stage liver diseases. Severe changes in circulation system and internal environment may occur during transplant surgery and cause injury to many organs including brain. Specific mechanisms of brain injury associated with liver transplantation are not yet elucidated. Previous studies have shown that the JAK/STAT signal transduction pathways are involved in the development of the central nervous system, such as nerve cell proliferation, survival, differentiation, and it also have a role in the disease processes, including brain tumor, brain ischemia and other diseases of the central nervous system. In this study we investigate whether propofol plays an important role in protecting the hippocampus through JAK2/STAT3 pathway. Thirty-two healthy male Sprague-Dawley rats, were randomly divided into four groups (n=8). Sham operation group (group S), autogenous orthotropic liver transplantation group (group I), autogenous orthotropic liver transplantation+propofol treatment group (group P) and autogenous orthotropic liver transplantation+propofol+AG490 treatment group (group A). We evaluated histological damage, inflammation, oxidative stress and apoptosis in hippocampus using HE staining, light microscope, real-time PCR and western blot. The results showed that there was a significant damage of hippocampus in group I compared to the sham group as demonstrated by increased serum levels of S100β, NSE and the histological changes. However, an induction of propofol reduced the levels of MDA, TNFα, S100β, NSE and increased activity of SOD, IL-10, and attenuated the expression of JAK2 and STAT3, meanwhile. Consistently, pretreatment with JAK2/STAT3 pathway inhibitor AG490, decreased the levels of MDA, TNFα, S100β, NSE and increased activity of SOD, IL-10, and attenuated the expression of JAK2 and STAT3. These results reveal that autogenous orthotropic liver transplantation induces the activation of JAK2/STAT3 signaling pathway in hippocampus. Pretreatment with propofol attenuates autogenous orthotropic liver transplantation induces hippocampal injury via JAK2/STAT3 pathway.