Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of cancer treatment and is primarily driven by oxidative stress and mitochondrial dysfunction. Despite its clinical relevance, effective mechanism-based therapies remain limited. Vinpocetine, a neuroprotective compound, has shown antioxidant, anti-inflammatory, and mitochondrial function-preserving effects; however, its efficacy in CIPN remains unknown. This study aimed to evaluate the efficacy and underlying mechanisms of vinpocetine in a paclitaxel-induced CIPN mouse model. In behavioral tests, acute administration of vinpocetine alleviated mechanical hypersensitivity, whereas repeated treatment provided sustained relief from mechanical, thermal, and cold hypersensitivity. Mechanistically, vinpocetine reduced mitochondrial reactive oxygen species (ROS), restored SOD2 levels, and activated mitochondrial biogenesis via the PGC-1α-NRF1-TFAM pathway, as shown by Western blot analysis. In oxidative stress-induced pain models, vinpocetine also attenuated mechanical hypersensitivity, reinforcing its antioxidant properties. Voltage-sensitive dye imaging revealed reduced spinal neuronal hyperexcitability. Immunohistochemistry analysis further demonstrated reduced expression of AMPA and PKC-α in NeuN-positive neurons. This preclinical study is the first to demonstrate that vinpocetine alleviates CIPN by enhancing mitochondrial biogenesis, reducing oxidative stress, and suppressing neuronal excitability in the spinal cord. These results provide mechanistic insights into its effects on CIPN and support further translational research in this indication.