Diabetes is a common metabolic disease whose hyperglycemic state can induce various complications, including central nervous system complications. There is evidence which suggests that oxidative stress has a key role in the pathogenesis of diabetes and its complications. Autophagy is one of the main routes to eliminate damaged components in cells in response to oxidative stress. However, excessive autophagy causes a distinct type of cell death involved in the pathogenesis of multiple diseases, such as diabetes. This study aimed to investigate the effect of melatonin on the autophagy in the prefrontal cortex of streptozotocin-induced type 1 diabetic rats. The expressions of coiled-coil, myosin-like BCL2 interacting protein (Beclin-1) mRNA, Microtubule-associated protein 1A/1B-light chain 3 (LC3), and sequestosome 1 (SQSTM1)/p62 mRNA are investigated by real-time PCR. Rats were divided into four groups: the control group (CON), the diabetes (DM) group, the diabetes supplemented with melatonin (DM+MEL) group, and the control supplemented with melatonin (CON+MEL) group. The results showed that the levels of Beclin-1, LC3, and P62 mRNA were markedly increased in the DM group compared to the CON group. In contrast, the mRNA levels of these entire genes were decreased significantly in the DM+MEL group compared to the DM group. These findings suggest that melatonin exhibits a neuroprotective effect by inhibiting exessive autophagy. Therefore, melatonin might be a potential agent for the prevention of diabetic-induced central nervous system complications.Acknowledgement: This study was supported by a research grant from HRH Princess Mahachakri Sirindhorn Medical Center, Faculty of Medicine, Srinakharinwirot University (Contract No.268/2565).