An increasing number of studies have found that use of traditional anesthetics may lead to cognitive impairment of the immature brain. Our previous studies verified that cyclin-dependent kinase 5 (CDK5) plays a role in sevoflurane-induced cognitive dysfunction. Autophagy was shown to protect against anesthesia-induced nerve injury. Therefore, the current study aimed to ascertain if autophagy participates in anesthesia-induced neurotoxicity. In this study, primary hippocampal neurons were isolated and utilized for experiments in vitro. We also performed in vivo experiments with 6-day-old wild-type mice treated with or without roscovitine (Rosc, a CDK5 inhibitor) or 3-methyladenine (3-Ma, an autophagy inhibitor) after exposure to sevoflurane. We used the Morris water maze to analyze cognitive function. Immunohistochemical staining was used to assess pathologic changes in the hippocampus. The results showed that suppressing CDK5 reversed sevoflurane-induced nerve cell apoptosis both in vivo and in vitro and demonstrated that inhibits CDK5 activation promoted Sirtuin 1 (Sirt1) expression, which functions importantly in induced autophagy activation. Suppression of Sirt1 expression inhibited the protective effect of Rosc on sevoflurane-induced nerve injury by inhibiting autophagy activation. Our in vivo experiments also found that pretreatment with 3-Ma attenuated the protective effect of Rosc on sevoflurane-induced nerve injury and cognitive dysfunction. We conclude that inhibits CDK5 activation restored sevoflurane-induced cognitive dysfunction by promoting Sirt1-mediated autophagy.