One of the most important mechanisms linking obstructive sleep apnea (OSA) to insulin resistance and type 2 diabetes involves oxidative stress. We examined whether oxidative stress-induced pancreatic injury could be reversed by the antioxidant melatonin (MEL) in male C57BL/6J mice with intermittent hypoxia(IH). Male C57BL/6J mice were randomly divided into four groups: a vehicle-treated normoxic group (CON), a melatonin-treated normoxic group (MEL), a vehicle-treated intermittent hypoxic group (IH) and a melatonin-treated intermittent hypoxic group (IH+MEL). The vehicle (2% ethanol in normal saline) or melatonin (10 mg/kg) was intraperitoneally administered daily for 2 weeks, 30 min before normoxia (intermittent air) or IH exposure. Insulin tolerance, plasma insulin levels, malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity, glutathione (GSH) concentrations, β-cell apoptosis, and mRNA expression of pancreatic antioxidant enzymes glutathione peroxidase 1 (GPx1) and mitochondrial type superoxide dismutase (MnSOD) were measured in all groups. IH significantly increased the level of insulin resistance, plasma insulin content, MDA, and β-cell apoptosis when compared to the CON and MEL groups; however, SOD activity, GSH concentrations and GPx1 and MnSOD mRNA levels decreased in the IH animals. In the melatonin-treated IH mice, all of the above mentioned indices were significantly different from those in the IH mice, trending towards normal values. These results indicate that the oxidative stress induced by IH can lead to pancreatic injury, and that the injury can be partially inhibited by the antioxidant melatonin. These observations may be important to the understanding of the pathological changes noted with OSA.