Viral infection is one of the important factors for the pathogenesis of type 1 diabetes. Particularly, in fulminant type 1 diabetes, rapid β-cell destruction is suggested to be triggered by viral infection. Recently, glucagon-like peptide 1 (GLP-1) receptor agonists have been reported to have direct beneficial effects on β-cells, such as anti-apoptotic effect, increasing β-cell mass, and improvement of β-cell function. However, their effects on β-cell destruction induced by viral infections have not been elucidated. In this study, we used an encephalomyocarditis virus (EMCV)-induced diabetic model mouse to show that a GLP-1 receptor agonist, exendin-4, prevents β-cell destruction. Nine-week-old male DBA/2 mice were intraperitoneally injected with EMCV (200 plaque forming units (PFU) mouse −1). Low (20 nmol kg −1 d −1) or high (40 nmol kg −1 d −1) doses of exendin-4 were administered for 10 d, starting from 2 d before the infection, and the rate of diabetic onset was evaluated. In addition, the number of infiltrating macrophage per islet and the ratio of β-cell area to islet area were determined. The effects of exendin-4 on infected β-cells and macrophages were investigated by using MIN6 and RAW264 mouse macrophages. The incidence of diabetes was significantly lower in the high-dose exendin-4-treated group than in the control group. Furthermore, the β-cell area was significantly more preserved in the high-dose exendin-4-treated group than in the control. In addition, the number of macrophages infiltrating into the islets was significantly less in the high-dose exendin-4-treated group than in the control group. In vitro, exendin-4 reduced β-cell apoptosis, and tumor necrosis factor α (TNFα), interleukin β (IL-β), and inducible nitric oxide synthase (iNOS) production of infected or lipopolysaccharide (LPS)-stimulated macrophages. These results suggested that exendin-4 limits β-cell destruction by protecting β cells and reducing the inflammatory response of macrophages.