Prevalence of neuropathic pain is high after major surgery. However, effective treatment for preventing neuropathic pain is lacking. Here we report that perisurgical treatment of neuroprotectin D1/protectin D1 (NPD1/PD1), derived from docosahexaenoic acid, prevents nerve injury‐induced mechanical allodynia and ongoing pain in mice. Intrathecal post‐treatment of NPD1/PD1 also effectively reduces established neuropathic pain and produces no apparent signs of analgesic tolerance. Mechanistically, NPD1/PD1 treatment blocks nerve injury‐induced long‐term potentiation, glial reaction, and inflammatory responses, and reverses synaptic plasticity in the spinal cord. Thus, NPD1/PD1 and related mimetics might serve as a new class of analgesics for preventing and treating neuropathic pain. Ann Neurol 2013;74:490–495