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Objective To investigate the effect of hyperbaric oxygen (HBO) therapy on consciousness and prognosis in patients with prolonged disorders of consciousness (pDOC) after hypoxic-ischemic brain injury (HIBI). Methods Clinical data of 78 pDOC patients after HIBI treated in the General Hospital of Southern Theater Command from January 2010 to June 2019 were collected and analyzed retrospectively. In accordance with their treatment, they were divided into control group (n=19) and HBO group (n=59). Then, the HBO group was further assigned into long-course subgroup (n=21) and short-course subgroup (n=38) according to whether the course of disease was longer than 3 months. The patients in the control group received only routine treatment, while those in the HBO group got HBO therapy on the basis of routine treatment. Gender, age, GOS score at admission, and Coma Recovery Scale-Revised (CRS-R) score at admission and discharge were recorded. Glasgow Outcome Scale was used for follow-up survey in 1 year after discharge. Results The HBO group had significantly higher CRS-R score at discharge (11.51±6.33 vs 8.05±4.81), larger proportion of those achieving better consciousness (66.10% vs 26.32%) when compared with the control group (P < 0.05). In 1 year after discharge, the GOS score was significantly higher (2.53±1.12 vs 1.42±0.69) and lower mortality (20.34% vs 68.42%) in HBO group than the control group (P < 0.05). Moreover, in the short-course subgroup, the CRS-R score at discharge was obviously higher (12.45±6.73 vs 8.05±4.81), the proportion of patients with consciousness improved was larger (71.05% vs 26.32%), the GOS score in 1 year after discharge was higher (2.58±1.13 vs 1.42±0.69), and lower mortality rate was lower (18.42% vs 68.42%) when compared with the control group (P < 0.05). And in the long-course subgroup, similiar results of above indicators were seen in comparison with the control group (57.14% vs 26.32%; 2.43±1.12 vs 1.42±0.69; 23.81% vs 68.42%; P < 0.05). Conclusion HBO therapy can improve the consciousness of patients with pDOC after HIBI, even if the course exceeds 3 months. Further more, HBO therapy can improve long-term prognosis and reduce mortality rate in these patients.