ABSTRACT The mechanisms of spinal cord-wide structural and functional disruption in diabetic patients remain elusive. This study evaluated histopathological alterations of the spinal cord cytoarchitecture in T2DM model of rats and assessed the potential ameliorating effect of exenatide "a potent GLP-1 analogue". Thirty male rats were allocated into three groups; I (control), II (Diabetic): T2DM was induced by high fat diet for 8 weeks followed by a single I. P injection of STZ (25 mg/kg BW) and III (Diabetic/Exenatide): T2DM rats injected with exenatide (10 μg/Kg, S.C. twice daily for 2 weeks). Neurobehavioral sensory and motor tests were carried out and glycemic control biomarkers and indices of insulin resistance and sensitivity were measured. In addition, the spinal cord was processed for histological and immunohistochemical studies besides assessing its tissue homogenate levels of pro-inflammatory/anti-inflamatory cytokines and oxidant/antioxidant biomarkers. Moreover, RT-qPCR was performed to measure the expression of proapoptotic/antiapoptotic and neurotrophic genes. The diabetic rats exhibited thermal hyperalgesia, mechanical allodynia and decreased locomotor activity along with increased serum glucose, insulin, HbA1c, HOMA-IR while, quantitative insulin sensitivity check index (QUICKI) was decreased. Also, IL-1β, NF-kB, MDA increased while IL-10, SOD activity and β-endorphin decreased in the spinal tissue. Up regulation of caspase-3 and down regulation of Bcl-2, nerve growth factor (NGF) and glial cell-derived neurotrophic (GDNF) in diabetic rats. Also, they exhibited histopathological changes and increased CD68 positive microglia and Bax immunoreactivity in the spinal cord. Subsequent to exenatide treatment, most biomolecular, structural and functional impairments of the spinal cord were restored in the diabetic rats. In conclusion, the neuro-modulating effect of exenatide against diabetic-induced spinal cord affection warrants the concern about its therapeutic relevance in confronting the devastating diabetic neuropathic complications.