Postoperative cognitive dysfunction (POCD) is a neurological sequela of surgery and anesthesia. It occurs with high incidence in the aged population. Neuroinflammation is considered one of the least controversial culprits contributing to this postsurgical cognitive impairment, although it is a matter of debate as to why this complication occurs frequently in geriatric individuals. It is unclear how neuroinflammation is activated in aged populations following exposure to anesthesia and surgical procedures. In this study, we investigated the role of sirtuin 1 (SIRT1) in neuroinflammatory priming and cognitive deficits in aged rats after anesthesia and surgery. Our findings demonstrated that the hippocampal expression of SIRT1 decreased with age. The trend of declining SIRT1 expression further deteriorated in aged rats after exposure to anesthesia and surgery. Furthermore, we found that decreased SIRT1 was associated with downregulated expression of DNA methyltransferase 1 (DNMT1) and upregulated acetylated-nuclear factor kappa B (ac-NF-kappa B) expression, resulting in microglial activation and increased proinflammatory cytokines in the hippocampus of aged rats. Interestingly, our results showed that pretreatment with resveratrol, a SIRT1 agonist, mitigated the neuroinflammatory response and microglial activation and improved cognitive performance in the context fear-conditioning test and Morris water maze. Taken together, our findings suggest that anesthesia and surgery-induced inhibition of hippocampal SIRT1 expression is involved in the activation of neuroinflammation and cognitive impairment in aged rats and that activating SIRT1 might paved a promising path to preventing this postsurgical sequela.