Objective: To investigate the effects of low-dose hydrocortisone on brain dysfunction in LPS-induced sepsis rats and the role of nuclear factor kappa B (NF-κB) signal transcription pathway in the pathogenesis. Methods: Fifty-four rats were randomly divided into 3 gro ups: control group (A group, n = 6), model group (B group, n = 24), low-dose HC treatment group (C group, n = 24). The septic rat model was established by intra-peritoneal injection of LPS (1 mg/kg), the intervention was by caudal vein injection of low-dose HC (6 mg/kg), each of B and C group was subdivided into 2, 8, 16, 24 hours after LPS injection (n = 6). At serial time points, the animals in each group were sacrificed, brain tissue samples were harvested to determine NF-κB, IκB expression in hippocampus by immunohistochemistry. Also, the changes of behaviors were observed and the histopathological changes were investigated by Nissl stain. Results: In model group (B group): lethargy, anorexia, tachypnea , piloerection, loss of body weight were all more obvious than control groups. Nissl stain showed significant histopathological changes; NF-κB expression was up regulated compared with control group (P < 0.05), IκB expression showed a down regulation firstly and escalated gradually before the peak of 8 hours time point peak (P < 0.05). Low-dose HC treatment group (C group): the changes of behaviors, Nissl histopathological changes showed improvements compared with model group. NF-κB expression was down regulated compared with model group (P < 0.05) whilst IκB expression was prominently enhaned (P < 0.05). Conclusion: Low-dose HC inhibited the NF-κB expression by inducing the IκB expression, and then causing brain dysfunction in the septic rats. The NF-κB/IκB signal transcription pathway may have very important role in the pathogenesis of brain dysfunction in sepsis.