Neuropathic pain is one of the most intractable diseases. The lack of effective therapy measures remains a critical problem due to the poor understanding of the cause of neuropathic pain. The aim of this study was to investigate the effect of dexmedetomidine (Dex) in trigeminal neuropathic pain and the underlying molecular mechanism in order to identify possible therapeutic targets. We used a chronic constriction injury (CCI) model of mice to investigate whether Dex prevents neuropathic pain and the inflammation response. The α 2-adrenoceptors (α2AR) inhibitor BRL44408 and adenovirus for knocking down High mobility group box 1 (HMGB1) was administrated to confirm whether Dex exert its effect through targeting α2AR and HMGB1. The results indicated that Dex significantly inhibited CCI induced neuropathic pain through targeting α2AR and HMGB1. Dex inhibited the inflammatory response through decreasing the release and the mRNA expression of IL-1β, IL-6, and TNF-ɑ while increasing that of IL-10. Moreover, Dex participates in the regulation of HMGB1, Toll-like receptor 4 (TLR4), NFκb (p-65) expression and the phosphorylation of IκB-ɑ. In conclusion, Dex could relieve neuropathic pain through α2AR and HMGB1 and attenuate inflammation response.