Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of unknown etiology characterized by degradation of cartilage and bone, accompanied by unimpeded proliferation of synoviocytes of altered phenotype. In the present study, we investigated the involvement of the glucagon-like peptide 1 (GLP-1) receptor on human fibroblast-like synoviocytes (FLS) in the pathogenesis of RA using the selective GLP-1 agonist exenatide, a licensed drug used for the treatment of type 2 diabetes. Our results indicate that exenatide may play a role in regulating tumor necrosis factor-α-induced mitochondrial dysfunction by increasing mitochondrial membrane potential, oxidative stress by reducing the production of reactive oxygen species, the expression of NADPH oxidase 4, expression of matrix metalloproteinase (MMP)-3 and MMP-13, release of proinflammatory cytokines including interleukin-1β (IL-1β), IL-6, monocyte chemoattractant protein-1, and high-mobility group protein 1, as well as activation of the p38/nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α/nuclear factor κB signaling pathway in primary human RA FLS. These positive results indicate that exenatide may have potential as a therapeutic agent for the treatment and prevention of RA. © 2019 IUBMB Life, 9999(9999):1-9, 2019.