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Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is a commonly used hypoglycemic agent in clinical practice; it inhibits reactive oxygen species-induced pancreatic β-cell apoptosis. N 6 -methyladenosine (m 6 A) is produced by the methylation of RNA N6 residues and has recently been shown to play a crucial role in the regulation of islet β-cell growth and development. However, the involvement of m 6 A methylation in the β-cell protective effects of exenatide has not been clarified. In this study, the m 6 A-methylated RNA content and methyltransferase-like 3 (METTL3) expression levels in NIT-1 cells and primary mouse islets were found to significantly decrease following treatment with hydrogen peroxide (H 2 O 2 ). Treatment with exenatide induced an increase in m 6 A content and METTL3 expression in the H 2 O 2 -treated NIT-1 cells and islets. Moreover, METTL3 silencing resulted in NIT-1 cell apoptosis under normal culture conditions. METTL3 upregulation significantly ameliorated H 2 O 2 -induced apoptosis in NIT-1 cells and primary islets. Furthermore, the anti-apoptotic effects of exenatide were obviously reversed by METTL3 knockdown. In conclusion, these findings suggest that exenatide elicits its anti-apoptotic effects in pancreatic β-cells by promoting m 6 A methylation through the upregulation METTL3 expression., (Copyright © 2022. Published by Elsevier B.V.)