Recent studies have shown that dexmedetomidine exerts an anti-inflammatory effect by reducing serum levels of inflammatory factors, however, the up-stream mechanism is still unknown. The transcription factor NF-B enters the nucleus and promotes the transcription of its target genes, including those encoding the pro-inflammatory cytokines IL-6 and TNF-. In this study, we established a rat model that simulates a clinical surgical procedure to investigate the anti-inflammatory effect of perineural administration of dexmedetomidine and the underlying mechanism. Dexmedetomidine reduced the sciatic nerve levels of IL-6 and TNF- at both the mRNA and protein level. Dexmedetomidine also inhibited the translocation of activated NF-B to the nucleus and the binding activity of NF-B. The anti-inflammatory effect is confirmed to be dose-dependent. Finally, pyrrolidine dithiocarbamate also reduced the levels of IL-6 and TNF- and the activation of NF-B. In conclusion, dexmedetomidine inhibited the nuclear translocation and binding activity of activated NF-B, thus reducing inflammatory cytokines.