Inflammation‐associated oxidative stress contributes to hepatic ischemia/reperfusion injury (IRI). Detrimental inflammatory event cascades largely depend on activated Kupffer cells (KCs) and neutrophils, as well as proinflammatory cytokines, including tumor necrosis factor α (TNF‐α) and interleukin (IL) 18. The aim of our study was to evaluate the effects of IL 18 binding protein (IL 18Bp) in hepatic IRI of mice. Thirty C57BL/6 mice were allocated into 3 groups: sham operation, ischemia/reperfusion (I/R), and I/R with intravenous administration of IL 18Bp. Hepatic ischemia was induced for 30 minutes by Pringle's maneuver. After 120 minutes of reperfusion, mice were euthanized, and the liver and blood samples were collected for histological, immunohistochemical, molecular, and biochemical analyses. I/R injury induced the typical liver pathology and upregulated IL‐18 expression in the liver of mice. Binding of IL 18 with IL 18Bp significantly reduced the histopathological indices of I/R liver injury and KC apoptosis. The I/R‐induced increase of TNF‐α, malondialdehyde, aspartate aminotransferase, and alanine aminotransferase levels was prevented in statistically significant levels because of the pretreatment with IL 18Bp. Likewise, blocking of IL 18 ablated the I/R‐associated elevation of nuclear factor kappa B, c‐Jun, myeloperoxidase, and IL 32 and the up‐regulation of neutrophils and T‐helper lymphocytes. Administration of IL 18Bp protects the mice liver from I/R injury by intervening in critical inflammation‐associated pathways and KC apoptosis. Liver Transpl 22:237‐246, 2016. © 2015 AASLD.