OBJECTIVE： To investigate the protection role and mechanisms of salidroside （SALD） on acetaminophen （APAP）-induced liver injury model mice. METHODS： 60 mice were randomly divided into normal group （normal saline）， model group （normal saline）， positive group （acetylcysteine， 150 mg/kg）， SALD low-dose， medium-dose and high-dose groups （100， 200， 300 mg/kg）， with 10 mice in each group. Except for normal group， other groups were given APAP 500 mg/kg intragastrically to induce liver injury model. 1 h before modeling， mice were given relevant medicine intrgastrically for consecutive 5 d. After medication， the serum contents of ALT， AST， ALP and LDH were determined， and the pathohistological changes of the liver tissue were observed by HE staining. The protein expressions of Keap1 （in tranuclear）， Nrf2 （in tranuclear）， HO-1 （in tracytoplasm）， NQO1 （in tracytoplasm） and GCLC （in tracytoplasm） in liver tissue were determined by Western blot assay. RESULTS： Compared with normal group， serum contents of ALT， AST， ALP and LDH in model group were increased significantly （P＜0.01）. The liver lobuli hepatis disorder and difficult to recognize， liver cell eosinophilic necrosis and other lesions were found in liver tissue. The protein expressions of Nrf2， Keap1， HO-1 and GCLC in liver tissue were decreased significantly （P＜0.05）. Compared with model group， above indexes of all groups were improved significantly （P＜0.05 or P＜0.01）， except that the decrease of LDH content in serum of mice in SALD low-dose group and the expression improvement of Nrf2 and Keap1 in liver tissue were not significant in positive group. The expression of NQO1 protein in liver tissue of mice was increased significantly in administration groups （P＜0.05 or P＜0.01）； pathohistological exchange of liver tissue in mice was improved in adminstration groups to different extent. CONCLUSIONS： SALD can protect APAP-induced liver injury； the mechanism of which may be associated with promoting Keap1， Nrf2 into the of nucleu and strengthening the protein expression HO-1， NQO1， GCLC in liver tissue.