Diabetic neuropathy (DN) is the most common diabetes complication. This study aimed to investigate the possible neuroprotective effects of the n-BuOH extract of Capparis spinosa (BECS) against DM-neuropathy induced with streptozotocin (STZ) and explore its phytoconstituents. From our results, BECS showed no toxicity against C6 brain cancer cell lines. The treatment of male Swiss albino rats with BECS (200 mg/kg) for a period of 28 days significantly attenuated the adverse effects of STZ-induced diabetes (60 mg/kg). A decrease in blood glucose was noted in the BECS-STZ group, associated with a significant (p<0.01) improvement in serum and brain insulin levels. The BECS-treated group showed a significant (p<0.01) improvement in serum C-peptide, serum AGE and serum CK-BB levels. BECS was also successful in restricting HbA1c in STZ-treated rats. Furthermore, a resurrection of neuronal membrane integrity was manifested in the BECS+STZ group, as evidenced by increased brain LDH activity and reduced brain MDA level. Treatment of STZ-treated rat with BECS was also able to significantly (p<0.01) regulate markers of brain dysfunction (AChE and BChE activities and glutamate ,dopamine levels). Additionally, treatment of rats with BECS efficacy restored the GSH level and GSH-system enzymes towards normal levels. Regarding the levels of (IL-6, TNF-α, and NO) produced by diabetogenic effects of STZ, the BECS successfully regulated these inflammatory mediators. From all these results, the neuroprotective effect of BECS could be due to its richness in polyphenols identified by LC-MS/MS (both positive and negative modes) analysis, mainly chlorogenic acid and rutin, as well as the synergistic interactions of all contents.