Objective To investigate the effects of Radix Tetrastigma hemsleyani flavone ( RTHF) on pyroptosis and ferroptosis in mice with sepsis liver injury via activation of the Nrf2 signaling pathway and its molecular mechanism. Methods KM mice were divided randomly into six groups: a control group, model group, positive control group (dexamethasone 10 mg / kg) and low, middle and high dose RTHF groups. Mice in the RTHF groups were pretreated with intraperitoneal injections of 60, 90 and 120 mg / kg RTHF for 7 d, while mice in the positive control group were pretreated by intraperitoneal injection of dexamethasone 10 mg / kg for 7 d. An acute liver injury model of sepsis was established by intraperitoneal injection of lipopolysaccharide ( 10 mg / kg ). The mice were euthanized 24 h later and liver and blood samples were collected. The therapeutic efficacy and pharmacological mechanism of RTHF against sepsis-induced acute liver injury were evaluated by observations of gross specimens,histopathology, biochemical examination, and molecular biology examinations. Results Compared with the model group, low, middle and high dose RTHF groups significantly reduced serum levels of alanine transaminase(ALT), aspartate aminotransferase(AST), interleukin (IL)-6, tumor necrosis factor-α(TNF-α), IL-1β, and IL-18 and liver levels of malondialdehyde(MAD), Fe^{2 +}, and reactive oxygen species(ROS) (P<0. 01, P<0. 05), significantly increased liver superoxide dismutase(SOD) and glutathione(GSH) levels (P<0. 01, P<0. 05), improved liver tissue pathology and inflammatory infiltration, and decreased the liver index. RTHF also up-regulated the expression of Nrf2 protein, Nrf2 and heme oxygenase-1(HO-1) levels in the nucleus, and solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase-4 protein(GPX4) expression (P<0. 01, P<0. 05), and down-regulated the expression of Cleaved-Caspase-1, GSDMD-NT, as well as Keap1, NLRP3, Caspase-1, Cleaved-Caspase-1,GSDMD and GSDMD-NT (P<0. 01, P<0. 05). Conclusions RTHF can reduce the release of inflammatory factors, relieve oxidative stress, inhibit ferroptosis and NLRP3-mediated pyroptosis by activating the Nrf2 signaling pathway, and may thus have protective effects against lipopolysaccharide-induced hepatic injury in mice with sepsis.