The purpose of this study was to investigate the hepatoprotective effect of alpha-mangostin (alpha-MG) on lipopolysaccharide/D-galactosamine (LPS/D-Ga1N)-induced acute liver failure and discover its potential mechanisms in mice. The results showed that alpha-MG could attenuate LPS/D-Ga1N-induced liver pathological injury, and decrease the hepatic malondialdehyde (MDA) level, serum alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor (TNF-alpha), interleukin-1 beta and 6 (IL-1 beta, IL-6) levels and recovery hepatic glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) activities. The results also indicated that alpha-MG inhibited LPS/D-Ga1N-induced toll-like receptor 4 (TLR4) expression and NF-kappa B activation. In addition, alpha-MG up-regulated the expressions of Nrf2 and heme oxygenase-1 (HO-1). In conclusion, the results indicated that alpha-MG could protect against LPS/D-Ga1N-induced liver failure by activating Nrf2 to induce antioxidant defense and inhibiting TLR4 signaling pathway to induce anti-inflammatory effect