Management of painful peripheral neuropathies remains challenging, since patients with chronic pain respond poorly to the available pharmacopeia. In recent years, the G‐protein‐coupled receptor neurotensin (NT) type 2 (NTS2) emerged as an attractive target for treating transitory pain states. To date, however, there is no evidence for its role in the regulation of chronic peripheral neuropathies. Here, we found that NTS2 receptors were largely localized to primary afferent fibers and superficial dorsal horns. Changes in the time course of the gene expression profile of NT, NTS1, and NTS2 were observed over a 28‐d period following the sciatic nerve constriction [chronic constriction injury (CCI) model]. We next determined the effects of central delivery of selective‐NTS2 agonists to CCI‐treated rats on both mechanical allodynia (evoked withdrawal responses) and weight‐bearing deficits (discomfort and quality‐of‐life proxies). The NTS2 analogs JMV431, levocabastine, and β‐lactotensin were all effective in reducing ongoing tactile allodynia in CCI‐treated rats. Likewise, amitriptyline, pregabalin, and morphine significantly attenuated CCI‐induced mechanical hypersensitivity. NTS2 agonists were also efficient in reversing weight‐bearing and postural deficits caused by nerve damage, unlike reference analgesics currently used in the clinic. Thus, NTS2 agonists may offer new treatment avenues for limiting pain associated with peripheral neuropathies and improve functional rehabilitation and well‐being.— Tétreault, P., Beaudet, N., Perron, A., Belleville, K., René, A., Cavelier, F., Martinez, J., Stroh, T., Jacobi, A. M., Rose, S. D., Behlke, M. A., Sarret, P., Spinal NTS2 receptor activation reverses signs of neuropathic pain. FASEB J. 27, 3741–3752 (2013). www.fasebj.org