The aim of this study was to investigate the hepatoprotective effect of anethole (trans-anethole, 1), a major component of Foeniculum vulgare, and its molecular mechanism during ischemia/reperfusion (I/R). Mice were subjected to 60 min of partial hepatic ischemia followed by 1 and 6 h of reperfusion. Compound 1 (50, 100, and 200 mg/kg) or the vehicle alone (10% Tween 80-saline) was orally administered 1 h prior to ischemia. After 1 and 6 h of reperfusion, serum alanine aminotransferase, tumor necrosis factor-α, and interleukin 6 levels significantly increased, but these increases were attenuated by 1. Nuclear translocation of interferon regulatory factor (IRF)-1, release of high mobility group box (HMGB) 1 into the extracellular milieu, and the interactions between IRF-1 and histone acetyltransferase p300 increased after I/R. These increases were attenuated by 1. Compound 1 suppressed increases in toll-like receptor (TLR) 4, myeloid differentiation primary response gene 88 protein expression, phosphorylation of p38, extracellular signal-regulated kinase, c-Jun N-terminal kinase, nuclear translocation of nuclear factor kappa B, and phosphorylated c-Jun. The present findings suggest that 1 protects against hepatic I/R injury by suppression of IRF-1-mediated HMGB1 release and subsequent TLR activation.