Memory decline is characteristic of aging and age-related neurodegenerative disorders. This study was designed to investigate the protective effect of hyperbaric oxygen (HBO) against cognitive impairment induced by D-galactose (D-gal) in mice. D-gal was intraperitoneally injected into mice daily for 8 weeks to establish the aging model. HBO was simultaneously administered once daily. The results indicate that HBO significantly reversed D-gal-induced learning and memory impairments. Studies on the potential mechanisms of this action showed that HBO significantly reduced oxidative stress by increasing superoxide dismutase, glutathione peroxidase, and catalase levels, as well as the total anti-oxidation capability, while decreasing the content of malondialdehyde, nitric oxide, and nitric oxide synthase in the hippocampal CA1 region. HBO also inhibited advanced glycation end-product formation and decreased levels of tumor necrosis factor-α and interleukin-6. Moreover, HBO significantly attenuated D-gal-induced pathological injury in the hippocampus, as well as β-amyloid protein expression and retained BDNF expression. Furthermore, HBO decreased p16, p21 and p53 gene and protein expression in the hippocampus of D-gal-treated mice. In conclusion, the protective effect of HBO against D-gal-induced cognitive impairment was mainly due to its ability to reduce oxidative damage, suppress inflammatory responses, and regulate aging-related gene expression.