Acetaminophen (APAP) overdose may lead to the formation of oxidative stress, hepatocyte apoptosis and necrosis, and, eventually result in acute liver failure. Escin, a major extracted component of Aesculus hippocastanum, reportedly exerts anti-inflammatory, anti-edematous and anti-oxidant properties. Previous studies have demonstrated these protective effects of A. hippocastanum extracts on ischemia/reperfusion intestinal injury and endotoxin-induced lung injury. In this study, we aimed to evaluate the effect of escin on APAP-induced liver injury in mice. Mice were intraperitoneally administrated with APAP (300 mg/kg) or an equal volume of saline (control), followed by a treatment with various concentrations of escin (0, 0.5, 1, 2 and 4 mg/kg) for 30 min. The animals were sacrificed 16 h following APAP administration for serum and liver tissue assay. Escin treatment attenuated the damage of APAP-induced liver injury in a dose-dependent manner (0.5-4 mg/kg). Escin also attenuated the hepatic myeloperoxidase (MPO) activity and hepatic pro-inflammatory cytokines (i.e., TNF-α, IL-1β, IL-6 and IL-17). Furthermore, escin treatment decreased the hepatic phosphorylation expression of extracellular signal-regulated kinase (ERK). Our data indicates that escin shows protective effects on APAP-induced hepatotoxicity in a dose-dependent manner through anti-inflammatory mechanism and the inhibition of ERK signaling pathway.