Objective To investigate the effects of early intervention of hyperbaric oxygen （HBO） on the behavioral changes and the levels of transcription factor NF-E2-related factor 2 （Nrf2） and heme oxygenase-1 （heme oxygenase-1， HO-1） in the hippocampusin of post-traumatic stress disorder （PTSD） model rats. Methods A total of 32 male Sprague-Dawley rats were randomly divided into four groups with 8 in each group： sham group， HBO group， ESPS group and ESPS + HBO group. The rats in ESPS group and ESPs + HBO group were exposed to single prolonged stress for the establishment of PTSD models. The other two groups were placed in the same experimental environment but did not receive ESPS at the same time. 24 h later， rats placed in hyperbaric oxygen chamber and exposed to 100% oxygen at 2.5 atmospheric absolute or atmospheric air for 1 h each day for 5 consecutive days. 7 days after the end of the intervention， rats were experienced open field test， elevated plus maze test and fear conditioning test， then sacrificed and the levels of Nrf2 and HO-1 in the hippocampus were determined by Western blot. Results （1） There was no significant difference in the total distance between the each group （P ＞ 0.05）. The exploration time ［（20.52±9.25） s］ and the number of times （15.22±4.38） in the ESPS group were significantly lower than those in the sham group ［（44.94±14.49） s and （32.77±6.22）］， while the ESPS + HBO group ［（35.49±13.04） s and （21.50±5.98）］ were significantly higher than those in the ESPS group （P＜ 0.05）. （2） Compared with time spent in open arm ［（54.47±23.23） s］， the percentage of open arm stay time （17.91±8.11） % and the number of open arm entry （10.54±3.85） of sham group， the time spent in open arm ［（26.18±8.56） s］， the percentage of open arm stay time （7.23±4.24） % and the number of open arm entry （3.10±1.96） were significantly reduced in ESPS group. In ESPS + HBO group， the time spent in open arm ［（40.77±16.66） s］， the percentage of open arm stay time （13.66±8.81） % and the number of open arm entry （6.40±1.71） were significantly higher than those in ESPs group （P＜ 0.05）. （3） The freezing time induced by environmentally ［（183.21±25.83） s］ and sound ［（202.03±47.79） s］ in ESPS group were significantly higher than those in sham group and ESPs + HBO group （P＜0.05）. （4） The relative expression level of Nrf2 （0.23±0.08） and HO-1 （0.84±0.13） in hippocampus of ESPS group was significantly lower than that of sham group and ESPs + HBO group （P ＜ 0.05）. （5） There was no significant difference between sham group and HBO group in the above parameters （P ＞ 0.05）. Conclusions Early intervention with hyperbaric oxygen may reversed anxiety behaviors and cognitive impairment in rats exposed to PTSD paradigm by regulating the expression of Nrf2/HO-1 in the hippocampus.