Chemotherapy-induced peripheral neuropathy (CIPN) is a severe adverse effect that occurs secondary to anticancer treatments and has no known preventive or therapeutic strategy. Therapeutic hypothermia has been shown to be effective in protecting against central and peripheral nervous system injuries. However, the effects of therapeutic hypothermia on CIPN have rarely been explored. We induced lower back hypothermia (LBH) in an established paclitaxel-induced CIPN rat model and found that the paclitaxel-induced impairments observed in behavioral, electrophysiological, and histological impairments were inhibited by LBH when applied at an optimal setting of 24°C to the sciatic nerve and initiated 90 minutes before paclitaxel infusion. Lower back hypothermia also inhibited the paclitaxel-induced activation of astroglia and microglia in the spinal cord and macrophage infiltration into and neuronal injury in the dorsal root ganglia and sciatic nerves. Furthermore, LBH decreased the local blood flow and local tissue concentrations of paclitaxel. Finally, in NOD/SCID mice inoculated with cancer cells, the antiproliferative effect of paclitaxel was not affected by the distal application of LBH. In conclusion, our findings indicate that early exposure to regional hypothermia alleviates paclitaxel-induced peripheral neuropathy. Therapeutic hypothermia may therefore represent an economical and nonpharmaceutical preventive strategy for CIPN in patients with localized solid tumors.