Background: Diabetic peripheral neuropathy (DPN) is considered among the most common consequences of diabetes mellitus (DM). Spexin-14 amino acid peptide hormone- is expressed in brain and peripheral tissues. It plays an increasing importance in metabolic illnesses because of its contribution in energy homeostasis and food intake besides its anti-inflammatory, anti-oxidative, properties. This work aimed to investigate the possible ameliorative impact of spexin towards the development of DPN in type-2 DM model induced experimentally in rats. Methods: 24 male healthy albino rats, with body weights 160-180 gm, were categorized into 3 groups: group I control group. Group II (induced type II Diabetic group) included rats fed a high-fat fructose diet for 8 weeks then a single dose of streptozotocin (35 mg/kg BW, intraperitoneal). And Group III: DM + Spexin group (35 μg/kg/day). Tail cold allodynia test, Tail flick test, Rota rod test and Gait test (behavioral tests) were done. Glucose, insulin, lipid profile, inflammatory and oxidative stress mediators serum values were measured. Serum TNF-α and IL-1 were assessed by ELISA. Gene expression of BCL2, and Caspase-3 concentrations in isolated sciatic nerve were measured by RT PCR Analysis finally histopathological analysis. Results: Giving Spexin to diabetic rats ameliorated deterioration in neuropathic behavior tests, reduced serum levels of glucose, improvement in lipid profiles and insulin resistance with a significant restoration of antioxidant enzyme levels, IL1, and TNF. Furthermore, a significantly elevated expression of Bcl-2 and declined Caspase-3 gene expression. At last improvements in histopathological changes were confirmed and supported by the other findings. In summary, Spexin alleviated diabetic nephropathy via its inhibitory potentials on inflammation and apoptosis. Conclusion: SPX improves diabetes induced peripheral neuropathy and has hypoglycemic, hypolipidemic, antioxidant, anti-inflammatory properties.