Postoperative cognitive dysfunction (POCD) is a common syndrome with perioperative cerebral damage in elderly patients, displaying cognitive impairment and memory loss. Current studies revealed that anesthesia is one of the important causes for POCD occurrence. Recently, Ubiquitin-like with PHD and Ring Figner Domains 2 (Uhrf2) has been reported to play a crucial role in regulating DNA methylation and hydroxymethylation, which are closely connected with memory building and erasure. However, whether narcotic drugs can affect Uhrf2 to impact on DNA methylation and hydroxymethylation in POCD is poorly understood. In this study, we established the elderly POCD mouse model through treatment with sevoflurane, and observed the global DNA hydroxymethylated cytosine (5hmC) distribution alteration in hippocampus, amygdaloid nucleus and cerebellum compared to non-POCD and control. Furthermore, we also found that the expression of Uhrf2 was coincident with 5hmC change in different regions of brain. Finally, we observed that the 5hmC enrichment on the promoters of some important genes for neural protection and development, such as GDNF, BDNF, GCR, ACSS2 were down-regulated upon POCD. Taken together, we determine that anesthetic may result in the loss of global 5hmC through Uhrf2 suppression in brain and thereby impair the learning and memory ability for POCD occurrence.