Context: Inflammatory and immune pathways play a crucial role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Sitagliptin blocks the dipeptidyl peptidase-4 (DPP-4) enzyme, mechanisms that alter inflammatory pathways and the innate immune system, and by which Sitagliptin affects the pathogenesis of NAFLD weren’t previously discussed. Objective: This study aims to understand the interaction between Sitagliptin and innate immune response in order to meliorate NAFLD. Methods: Thirty- two Wistar male albino rats were categorised into four groups. Rats have received a standard diet or a high-fat diet either with or without Sitagliptin. Serum HMGB1, protein and mRNA expressions of hepatic TLR4 and NF-jB, inflammatory cytokines, and histopathological changes were analysed. Results: An ameliorative action of Sitagliptin in NAFLD was demonstrated via decreasing HMGB1- mediated TLR4/NF-jB signalling in order to suppress inflammation and reduce insulin resistance. Conclusion: Sitagliptin may in fact prove to be a beneficial therapeutic intervention in NAFLD.