Objective To investigate the relation between the therapeutic effect of hyperbaric oxygen treatment and nuclear factor-κB (NF-κB) (P50) expression in the brain tissue in mice with traumatic brain injury (TBI). Methods A total of 120 SD rats were randomly divided into sham-operated, TBI model, normobaric oxygen and hyperbaric oxygen (0.2 MPa) groups, and in the latter 3 groups, TBI was induced using Feeney's method. At 6 h and 1, 3, 5, and 7 d following TBI (6 rats at each time point), the rats were sacrificed to observe the pathological changes in the brain tissues under light microscope and detect the expression of NF-κB (P50) using immunohistochemistry. Results The rats in hyperbaric oxygen group showed lessened brain edema as compared with those in TBI model and normobaric oxygen groups. Only trace amount of NF-κB (P50) expression was observed in the sham-operated group, while in the 3 groups with TBI, NF-κB (P50) expression began to increase as early as 6 h after TBI and kept increasing till reaching the peak level at 5 days. At each of the time points for observation, the expression ofNF-κB (PS0) in hyperbaric oxygen group was significantly higher than those in TBI and normobaric oxygen groups (P<0.05). Conclusion Hyperbaric oxygen treatment offers protection of the injured neural cells and promotes their repair in rats following TBI. Increased NF-κB (P50) expression in the brain tissue may serve as one of the pathways mediating the neuroprotective effect of hyperbaric oxygen treatment.