Inosine is a dietary supplement that is widely used for managing numerous central neurological disorders. Interestingly, recent experimental investigation of inosine revealed its potential to promote peripheral neuroprotection after sciatic nerve injury. Such investigation has guided the focus of the current study to expose the potential of inosine in mitigating diabetic peripheral neuropathy (DPN) in rats and to study the possible underlying signaling pathways. Adult male Wistar rats were arbitrarily distributed into four groups. In the first group, animals received saline daily for 15 days whereas rats of the remaining groups received a single injection of both nicotinamide (50 mg/Kg/i.p.) and streptozotocin (52.5 mg/Kg/i.p.) for DPN induction. Afterward, inosine (10 mg/Kg/p.o.) was administered to two groups, either alone or in combination with caffeine (3.75 mg/Kg/p.o.), an adenosine receptor antagonist. As a result, inosine showed a hypoglycemic effect, restored the sciatic nerve histological structure, enhanced myelination, modulated conduction velocities and maintained behavioral responses. Furthermore, inosine increased GLO1, reduced AGE/RAGE axis and oxidative stress which in turn, downregulated NF-κB p65 and its phosphorylated form in the sciatic nerves. Inosine enhanced Nrf2 expression and its downstream molecule HO-1, resulting in increased CAT and SOD along with lowered MDA. Moreover, pain was relieved due to suppression of PKC and TRPV1 expression, which ultimately lead to reduced SP and TGF-β. The potential effects of inosine were nearly blocked by caffeine administration; this emphasizes the role of adenosine receptors in inosine-mediated neuroprotective effects. In conclusion, inosine alleviated hyperglycemia-induced DPN via modulating GLO1/AGE/RAGE/NF-κB p65/Nrf2 and TGF-β/PKC/TRPV1/SP pathways.