DNA methylation and histone acetylation can be modified by various pathological or physiological factors such as hypoxia, thus influencing gene expression. In this study, we investigated the changes of global DNA methylation and histone acetylation and the related enzymes in rat brain after chronic cerebrovascular hypoperfusion by bilateral common carotid occlusion (2-VO) surgery. Colorimetric and immunohistochemistry staining were used to evaluate the global DNA methylation and histone acetylation levels, respectively. The expressions of DNA methyltransferase 1/3a (DNMT1/3a), methyl-CpG binding domain protein 2 (MBD2), histone deacetylase 3 (HDAC3) and acetyltransferase (HAT) were assessed by Western blot. We found that the level of global DNA methylation was decreased to 31.7% (P <0.01) of the sham-operated group at 10 days and increased by 30% (P <0.01) compared with the sham group at 90 days after 2-VO surgery. DNMT3a expression was down-regulated to 75.7% of the sham group, while MBD2 expression was up-regulated by 95% compared with sham group at 90 days after 2-VO. The histone H3 acetylation level was markedly decreased to 75.3% of the sham group at 10 days and 73.5% at 90 days after 2-VO, while no significant change was found for histone H4 acetylation. HDAC3 expression was markedly down-regulated to 36% of the sham group, whereas cAMP-response element binding protein expression was up-regulated by 33.6% compared with the sham group at 90 days after 2-VO. These results suggest that chronic cerebrovascular hypoperfusion influences global DNA methylation and histone acetylation levels through the related enzymes, and therefore might contribute to several neurodegenerative diseases.