The present study was to determine the protective effects of melatonin (MLT) against the damages of neuroendocrine-immune induced by lipopolysaccharide (LPS) in streptozotocin (STZ)induced diabetic rats, and to analyze the parameters related to diabetes and oxidative stress. A total of 70 male Sprague-Dawley rats were assigned to this experiment. 10 of rats received STZ intraperitoneally (i.p.) alone as diabetic control; 40 of rats as the Diabetes+LPS received STZ plus LPS i.p. after induction of diabetes with STZ, then assigned to sub-groups as MLT(0.1) (mg), MLT(1 mg), and Vehicle group, received two doses MLT and vehicle, i.p., respectively, q6h for 12h after LPS administration; and the remaining served as normal and LPS control. LPS significantly increased the serum levels of TNF-alpha and IL-6 in normal and diabetic rats: LPS also dramatically increased the plasma concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone. Both 0.1 and 1 mg/kg MLT doses significantly decreased the serum levels of TNF-alpha and IL-6. Significant inhibitory effects of MLT (1 mg/kg) were observed on the plasma concentrations of CRH, ACTH, and corticosterone of the HPA axis. The beneficial effects of MLT, such as the antioxidant activity and maintaining glucose homoeostasis, were also observed in this study, this resulted in a protective effect against the damages caused by LPS in STZ-induced diabetic rats. This finding probably provides a new approach for preventing the undesirable effects of the vicious cycle of hyperglycemia and stress factors such as severe infection in diabetic patients.