Neuropathic pain is elicited after a serious disorder of the nervous system and is along with the neural damage. It is usually chronic and challenging to treat. Transcription factor 4 (TCF4) is a key transcription factor of Wnt signaling system. Recent studies have shown that TCF4 interacts with β-catenin in the Wnt signaling pathway and coactivates downstream target genes in diverse systems. However, it is not well elucidated in the pathogenesis of neuropathic pain. In the present study, we investigated the role of TCF4 in the maintenance of neuropathic pain after chronic constriction injury (CCI) in rats. CCI induced persistent TCF4 upregulation in the dorsal root ganglion and spinal cord. Interestingly, TCF4 was mainly colocalized with neurons in the injured dorsal root ganglion and spinal cord on CCI day 7. Moreover, the expression patterns of β-catenin and glycogen synthase kinase-3β (GSK-3β) were parallel with that of TCF4 in vivo studies. Intrathecal injection of Wnt/β-catenin pathway inhibitor IWR-1-endo and TCF4 small interfering RNA (siRNA) significantly attenuated CCI-induced mechanical allodynia and heat hyperalgesia. The results suggest that TCF4 in the dorsal root ganglion and spinal cord is involved in the maintenance of CCI-induced neuropathic pain. Targeting TCF4 or Wnt/β-catenin signaling may be a potential treatment for chronic neuropathic pain.