Hypoxic preconditioning can induce endogenous protective mechanisms that increase the tolerance of nerve cells to hypoxia/ischemia. This protective mechanism involves changes in gene expression during the critical decision-making period between cell survival and death. DNA methylation, as a crucial mechanism for gene expression regulation, plays an essential role in hypoxia/ischemia tolerance. DNA methyltransferases (DNMTs) contribute to neuroprotection by influencing gene expression through the regulation of DNA methylation levels. Therefore, DNMTs have significant functions in the neuroprotection induced by hypoxic/ischemic preconditioning. This paper reviews the role of DNMTs in this process, providing insights into neuroprotection targeting DNMTs.