Objective To investigate the protective effect of wedelolactone ( Wed) against acetaminophen(APAP)-induced acute liver in mice. Methods A mouse model of APAP-induced liver injury was established. Thirty-twomale BALB/ c mice were randomly divided into normal, APAP, 10 mg/ kg Wed and 20 mg/ kg Wed groups (n = 8). Acolorimetric method was used to assay the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase(AST), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-PX) and superoxide dismutase(SOD) in mouse liver homogenates, and the serum levels of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6).Results In the model group,the serum levels of AST, ALT, IL-6 and TNF-α,and GSH and MDA in the liver homogenateswere significantly higher than those in the control group ( P < 0. 01). The levels of AST, ALT, SOD and GSH-PX in livertissue homogenates of the low- and high-dose Wed groups were significantly higher than those in the model group ( P <0. 01), and the levels of MDA and GSH in liver tissue homogenates and TNF-α and IL-6 in the serum of mice weresignificantly higher than those in the model group ( P < 0. 01). The levels of GSH-PX and SOD in the model group weresignificantly lower than those in the control group ( P < 0. 01). Histopathological examination using HE and TUNELstaining showed that Wed significantly reduced liver necrosis and apoptosis. Conclusions Wed has a protective effect on APAP-induced acute liver injury.