Chronic cerebral hypoperfusion is associated with cognitive decline in aging and age-related neurodegenerative disease. Epigenetic mechanisms are involved in the maintenance of long-term hypoxia-adapted cellular phenotypes. In the present study, the epigenetic signatures such as DNA methylation and histone acetylation, as well as S-adenosylmethionine (SAM) cycle using chronic cerebral hypoperfusion rat model were explored. Chronic cerebral hypoxia-induced global DNA hypermethylation associated with the increase of DNA methyltransferase (DNMT) 3A as well as alteration of SAM cycle. Meanwhile, an enhanced level of global histone H4 acetylation accompanied with the upregulation of histone acetyltransferase, p300/CREB-binding protein (CBP), and the downregulation of histone deacetylases (HDACs), was also observed. SAM could improve spatial capacity through the upregulation of acetylcholine and brain-derived neurotrophic factor (BDNF) rather than alteration of DNA methylation levels. In conclusion, we have demonstrated a genome-wide adjustment of DNA methylation and histone acetylation under chronic cerebral hypoxic conditions in a rat's brain. These epigenetic signatures may represent an additional mechanism to promote and maintain a hypoxic-adapted cellular responds with a potential role in memory deficits.