Radiation therapy is a widely used brain tumor treatment; however, it can cause significant effects on the central nervous system, including neurogenesis impairment, microglia activation, and oxidative stress, leading to brain injury. Hyperbaric oxygen therapy (HBOT) has been shown to benefit various neurological conditions, but its effect on radiation-induced brain injury damage remains limited. This study aims to investigate the impact of HBOT on radiation-induced neurogenesis impairment, microglia activation, and lipid peroxidation levels, and also aim to assess the therapeutic potential of HBOT on preventing irradiation-induced brain injury. This study used a rat model that delivered different doses (2, 4, 10 Gy) of whole-brain radiation therapy (WBRT). The rats were divided into two groups: one received HBOT, and the other acted as the control (normal baric air, NBA) group. HBOT was performed on day 8 of post-radiation once per day for five consecutive days a week for four weeks. The rats were subjected to different irradiation dosages as described, followed by administration of 5-chloro-2'-deoxyuridine (CldU) immediately at day 0 or day 0 to day 7 and 5-iodo-2'-deoxyuridine (IdU) at day 2 or day 14 to day 28 following WBRT to detect serially replicating cells. Then the rats underwent behavioral tests to assess their cognitive and motor function every week. Brain tissues were collected and analyzed to evaluate neurogenesis, microglia activation, lipid peroxidation, and antioxidant levels using immunofluorescence stain and ELISA on days 7 and 28 of post-WBRT. The radial maze was used to measure spatial learning and memory in rats. Compared with the 0 Gy-WBRT group, the 2 Gy-, 4 Gy-, and 10 Gy-WBRT groups of rats displayed a significant increase in latency. Seven days of post-WBRT, the newly proliferation cells (IdU positive) and serial replicating cells (CldU+IdU double positive) in the hippocampal dentate gyrus were significantly increased but were coupled with apoptosis. The alterations in the cellular composition of the dentate gyrus area were observed on days 7 and 28 post-WBRT, including increased newborn neuroblast and neuron, but half underwent apoptosis, which is associated with microglia phagocytosis and results in cognitive impairment. The lipid peroxidation was significantly increased on day 28 of post-WBRT. HBOT improves cognitive function by attenuating the WBRT-induced lipid oxidation, newly-formed cell apoptosis, and microglia phagocytosis. Our present study suggests that HBOT may have a potential role in mitigating the effects of irradiation-induced brain injury by maintaining neurogenesis and reducing lipid peroxidation.