BackgroundShort‐chain fatty acids have been reported to have anti‐inflammatory and antioxidant functions; whether isobutyrate, a short‐chain fatty acid, is protective against liver injury in a dextran sodium sulfate (DSS)‐induced colitis and its molecular mechanism is unknown. In this study, DSS was used to induce a liver injury from a colitis model in piglets, which was expected to prevent and alleviate DSS‐induced liver injury by feeding sodium isobutyrate in advance.ResultsThe results showed that sodium isobutyrate could restore DSS‐induced histopathological changes in the liver, inhibit the activation of the toll‐like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa‐B signaling pathway, and then reduce the DSS‐induced release of pro‐inflammatory cytokines tumor necrosis factor‐α, interleukin 1β, and interleukin 6, reducing inflammatory response. Moreover, we found that sodium isobutyrate could play an antioxidant and apoptosis‐reducing role by maintaining reduced mitochondrial function.ConclusionIn conclusion, sodium isobutyrate has a preventive and protective effect on liver injury in a DSS‐induced colitis. There is a potential application prospect for it in treating ulcerative‐colitis‐induced liver injuries. © 2024 Society of Chemical Industry.