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During liver transplantation, nonalcoholic steatohepatitis (NASH) aggravates ischemia/reperfusion (IR) injury by activating various kinases and subsequently releasing cytokines and chemokines. Nonetheless, the effect of the multikinase inhibitor sorafenib on IR liver injury in rats with NASH has never been explored. Our study was designed to determine this effect and associated mechanisms in NASH rats. Sorafenib was acutely administered to NASH rats with IR liver injury that were or were not chronically pretreated with the Rho-kinase–specific inhibitor fasudil. Then, the following were evaluated: mean arterial pressure; hepatic blood flow and microcirculatory dysfunction; hepatic inflammation (serum alanine aminotransferase); necrosis; apoptosis; leukocyte infiltration; CD45 staining; caspase levels and DNA fragmentation; various serum and hepatic cytokines; and proteins and genes of the Raf/mitogen-activated protein–extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase, and apoptosis pathways. In NASH rats with IR liver injury, hepatic inflammation, necrosis, apoptosis, leukocyte infiltration, and microcirculatory dysfunction were significantly attenuated by the acute administration of sorafenib through the inhibition of the hepatic release of macrophage inflammatory protein 2, keratinocyte chemoattractant, granulocyte-monocyte colony-stimulating factor, and hepatic caspase-3 and caspase-9 as well as DNA fragmentation. Furthermore, there was decreased expression of p-Raf1 (where p indicates the phosphorylated form), p-MEK1/2, p-ERK1/2, p-Rho-kinase, B cell lymphoma 2–associated death promoter, and B cell lymphoma 2–associated X protein at the protein and messenger RNA levels. Notably, the aforementioned beneficial effects of sorafenib were significantly abolished by chronic pretreatment with the Rho-kinase–specific inhibitor fasudil. This study demonstrated that the multikinase inhibitor sorafenib protects NASH rats from IR injury by interfering with the inflammation, necrotic, and apoptotic responses causing leukocyte-dependent hepatic microcirculatory dysfunction. The hepatoprotective effects of sorafenib seem to work through the inhibition of the Rho-kinase–dependent Raf/MEK/ERK pathway, which is up-regulated during IR injury in the livers of NASH rats. Liver Transpl 18:1371–1383, 2012. © 2012 AASLD.