Objective To investigate the effects of dexmedetomidine (DEX) on the nuclear factor-κB inhibitor protein kinase (IKK)/nuclear factor-κB inhibitor protein α (IκBα)/nuclear factor-κB (NF-κB) pathway and cognitive dysfunction in rats with post-traumatic stress disorder (PTSD).   Methods Rats were randomly divided into control group, model group, positive group and DEX group. Except for the control group, the PTSD model was constructed by single prolonged stress method  (SPS), and the corresponding drugs were given after the completion the model. Open field test and Morris water maze method  were used to detect the autonomous activity, learning and memory ability of rats; HE staining was used to observe the morphological characteristics of cerebral cortex and hippocampus; ELISA and Western blotting were used to detect the contents of interleukin (IL)-1β, IL-6, tumor necrosis factor α(TNF-α) and the expression levels of IKK, IκBα, purinergic ligand-gated ion channel 7 receptor (P2X7R), leucine-rich repeat domain protein 3(NALP3) in hippocampus; the NF-κB activity was assessed by electrophoretic mobility shift assay (EMSA).   Results Compared with the control group, the cerebral cortex and hippocampal CA1 region of model group were in structural disorders, nuclear pyysis and other pathological changes happend, learning and memory ability of rats decreased(P<0.05), contents of IL-1β, IL-6 and TNF-α, expression levels of IKK, IκBα, P2X7R and NALP3, NF-κB activity in hippocampus increased(P<0.05); Compared with the model group, the pathological phenomena in cerebral cortex and hippocampal CA1 area of rats in positive group and DEX group were in alleviated, and the changes of the above indexes were opposite to those of model group(P<0.05).   Conclusion DEX can significantly improve the autonomous activity ability and learning and memory ability in PTSD rats, reduce inflammatory reaction in hippocampus and improve cognitive dysfunction, which may be related to the down-regulation of IKK/IκBα/NF-κB pathway.