Vincristine is a frequently used antineoplastic drug for treating a variety of malignancies, although its usage has been restricted by the painful neuropathy it induces. A more profound comprehension of the pathogenesis of vincristine-induced painful neuropathy (VIPN) is crucial for developing efficient preventive and therapeutic approaches. With its well-established anti-inflammatory and immunomodulatory actions, curcumin (nanoemulsion form) was utilized in our work as a protective and therapeutic tool for VIPN. This study aims to clarify the mechanisms behind curcumin's neuroprotective effects against vincristine-induced neurotoxicity. For painful neuropathy induction, rats were injected with vincristine sulfate (150µg/kg/i.p.: once every two days) for five injections. For treatment, pregabalin (30 mg/kg/p.o.), curcumin (30mg/kg/p.o.) and curcumin nanoemulsion (30mg/kg/p.o.) were administered daily for 14 consecutive days. Our results showed that curcumin nanoemulsion significantly reduced cold allodynia and thermal hyperalgesia. It also increased the sciatic nerve levels of [CAT, SOD and IL-10] and the spinal cord PPAR-γ. Additionally, immunostaining of the sciatic nerve revealed a reduction in NF-κB expression and an increase in HSP70 expression. These findings suggest that curcumin has neuroprotective effects against VIPN, which might be attributed to its interference with the PPAR-γ, HSP70 and IL-10 signaling pathways.