Oroxylin A, a natural flavonoid isolated from Scutellariae baicalensis, has been reported to possess a wide spectrum of pharmacologic activities. However, the effects of oroxylin A on liver injury are poor understood. The purpose of this study was to investigate the effects of oroxylin A on acute liver injury in mice induced by lipopolysaccharide and/or D-galactosamine (LPS and/or D-GalN).Mice acute liver injury model was induced by LPS (50 μg/kg) and/or GalN (800 mg/kg). Serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-α levels, hepatic tissue histology, malondialdehyde content, and myeloperoxidase activity were analyzed. Meanwhile, nuclear factor kappa B (NF-κB), heme oxygenase-1 (HO-1), and nuclear factor erythroid2-related factor 2 (Nrf2) expression were detected by Western blotting.The results showed that oroxylin A dose-dependently inhibited LPS and/or GalN–induced serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-α levels. Hepatic malondialdehyde content and myeloperoxidase activity were also suppressed by oroxylin A. We also found that oroxylin A inhibited LPS and/or GalN–induced toll like receptor 4 (TLR4) expression and NF-κB activation. In addition, oroxylin A upregulated the expression of Nrf2 and HO-1 in a dose-dependent manner.In conclusion, oroxylin A protected against LPS and/or GalN–induced liver injury through activating Nrf2 and inhibiting TLR4 signaling pathway.