Inflammatory bowel disease (IBD) is often accompanied by secondary liver injury which further evolves into various hepatobiliary disorders. The pathogenesis of secondary liver injury involves many different mechanisms including inflammation, pyroptosis, oxidative stress, and heat shock response. Here, we tested the effect of administration of phenethyl isothiocyanate (PEITC) on secondary liver injury in DSS-induced IBD mice. PEITC supplementation reversed liver injury as determined by hepatic injury-related parameters and histopathological examinations. Severe hepatic inflammation with IBD, evidenced by ubiquitously distributed activated macrophages, increased secretion of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), enhanced expression of inflammation-related proteins (iNOS and COX-2), and augmented activation of the TLR4/NF-κB signaling pathway, was inhibited by PEITC treatment. PEITC also prevented IBD-induced increases in pyroptosis and oxidative stress in the liver. In addition, impairments of hepatic heat shock response elicited by IBD were restored by PEITC treatment. Taken together, these results suggested that PEITC may be effective as a therapeutic reagent to attenuate secondary liver injury caused by IBD.