AIM: To investigate the preventive effect and potential mechanism of bicyclol on sepsis-induced fulminant hepatitis (FH). METHODS: The FH model was established by lipopolysaccharide (LPS)/D-galactose (D-Gal), and mice were orally administrated with bicyclol and the survival rate within 24 h was recorded. The activities of glutamate aminotransferase (AST), alanine aminotransferase (ALT), catalase (CAT) and superoxide dismutase (SOD), and the content of glutathione (GSH) and malondialdehyde (MDA) in liver tissue were measured by chemiluminescence. The histopathological changes of liver were examined by HE and TUNEL staining. The levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) were measured using ELISA. The protein expression of nuclear transcription factor kappa B inhibitory protein α (IκBα), phosphorylated IκBα (p-IκBα), nuclear transcription factor kappa B (NF-κB), nuclear red blood cell 2 related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (NQO1), and heme oxygenase 1 (HO1) in liver tissue was examined by Western blotting. RESULTS: Pre-treatment with bicyclol improved survival ratio of FH mice, reduced ALT and AST activities, alleviated liver tissue lesions, and lowered Suzuki score. Meanwhile, the levels of TNF-α, IL-1β, IL-6 and MDA were reduced, the GSH level and CAT and SOD enzyme activities were increased, the protein expression of p-IκBα and nuclear NF-κB was down-regulated, and the protein levels of IκBα, nuclear Nrf2, NQO1 and HO1 were up-regulated. Moreover, post-treatment with Bicyclol also significantly reduced ALT and AST activities in FH mice. CONCLUSION: Bicyclol exhibited remarkable hepaprotective efects on FH caused by LPS/D-Gal, the potential mechanism underlying the anti-infammatory and antioxidative activities of Bicyclol might be associated with the suppression of NF-κB signaling pathway and the activation of Nrf2/NQO1/HO1 signaling pathway.