Recent studies have shown that hyperbaric oxygen (HBO) has a therapeutic effect on vascular dementia (VD); however, the exact mechanism remains unclear. This article aims to reveal the protective effects and underlying mechanisms of HBO on VD. A total of 158 patients with VD were prospectively included in the study and were randomly divided into control group and HBO group. The control group was given conventional treatment and the HBO group was treated with HBO in addition to conventional treatment. The following HBO protocol was practiced: 5 days per week, 60 min each, 100% oxygen at 2 standard atmospheric pressures for 12 weeks. The Mini-Mental State Examination (MMSE) scores and serum Humanin levels were detected before and after treatments in both groups. The baseline characteristics were not different dramatically between groups (p > 0.05). There was no significant difference in MMSE scores and serum Humanin levels between the two groups before treatment (p > 0.05). After treatment, compared with the control group, the MMSE scores and serum Humanin levels in the HBO group were significantly increased (p < 0.05). Spearman correlation analysis showed that the serum Humanin levels were positively correlated with MMSE scores (r = 0.409, p < 0.05) and this correlation was independent of baseline characteristics (β = 0.312, p < 0.05). HBO therapy can improve cognitive function in patients with VD, and its mechanism may be related to elevated serum Humanin levels.