The aim is to investigate the role of epigenetics in the irradiation-induced cognitive deficiency by observing the alterations of histone acetylation in the hippocampus of rats after irradiation. A signal dose of 2Gy and 30Gy 4MV electron beam were given to adult male Sprague-Dawley rats (150-200g, 4-5 weeks), this dose covered a dose range of clinical and experimental applications, and the animals were divided into 2Gy group, 30Gy group, and control group. After whole brain irradiation, the total protein was extracted from irradiated hippocampus and whole brain 30μm cryosections were cut by using a cryostat at day 7 and day 30. Western blot was performed and the brain sections were immunohistochemical stained. The alterations of histone H3 acetylation was observed and analyzed. To evaluate the consequence of whole brain irradiation on hippocampus-dependent memory formation, Morris water maze test, passive-avoidance test and open field test were performed. We show that both 2Gy and 30Gy 4MV electron beam whole brain irradiation induced significant decrease in histone H3 acetylation and different alterations of histone deacetylases (HDACs) in the hippocampus. We found a 25% reduction in histone H3 acetylation at day 7 (p < 0.01) and 5% reduction at day 30 (p < 0.05) after 2Gy irradiation. Compare to control, 30 Gy induced 5% reduction at day 7 and 13% reduction at day 30. Interestingly, we found that irradiation did not impair the expression of HDAC2, which has been indicated negatively regulates memory formation and synaptic plasticity. However, HDAC1 was increased. In Morris water maze test, passive-avoidance test and open field test, we confirmed whole brain irradiation lead to notable memory impairment at day 30 after irradiation. This study suggests that the alterations of histone H3 acetylation and HDACs after whole brain irradiation. Decreased histone H3 acetylation suggests altered hippocampal epigenetic signaling after whole brain irradiation. These results indicate epigenetics was involved in irradiation-induced memory deficiency, and alterations in chromatin structure may be a new possible molecular correlation of irradiation-induced cognitive deficiency.