BACKGROUND Perioperative neuro-cognitive disorders (PND) are preoperative and postoperative complications of multiple nervous systems, typically manifested as decreased memory and learning ability after surgery. It was used to replace the original definition of postoperative cognitive dysfunctions (POCD) from 2018. Our previous studies have shown that sevoflurane inhalation can lead to cognitive dysfunction in Sprague-Dawley rats, but the specific mechanism is still unclear. MATERIAL AND METHODS Thirty-six male Sprague-Dawley rats were randomly divided into 6 groups (n=6): the SD group was given 24-h acute sleep deprivation; Sevoflurane was inhaled for 2 h in the Sevo group. Two mL propofol was injected into the tail vein of rats in the Prop group. The rats in the SD+Sevo group and SD+Prop group were deprived of sleep before intervention in the same way as before. RESULTS We noted significant behavioral changes in rats treated with SIK3 inhibitors or tau phosphorylation agonists before propofol injection or sevoflurane inhalation, with associated protein levels and dendritic spine density documented. Sevoflurane anesthesia-induced cognitive impairment following acute sleep deprivation was more pronounced than sleep deprivation-induced cognitive impairment alone and resulted in increased brain SIK3 levels, increased phosphorylation of total tau and tau, and decreased acetylation modifications. After using propofol, the cognitive function returned to baseline levels with a series of reversals of cognitive dysfunction. CONCLUSIONS These results suggest that sevoflurane inhalation via the SIK3 pathway aggravates cognitive impairment after acute sleep deprivation and that propofol anesthesia reverses the effects of sleep deprivation by affecting modifications of tau protein.