Background: Sevoflurane inhalation initiated cognitive deficits implicated in mitochondrial dysfunction, synaptogenesis impairment and neuroinflammation. Egr2 plays a crucial role in maintaining cognitive function. Therefore, we attempted to clarify the potential correlation regarding Egr2 expression and cognitive deficits induced by sevoflurane administration. Methods: Animals received sevoflurane anesthesia, and the behavioral tests including Morris water maze, novel object recognition test and trace fear conditioning were performed. Then, the Golgi-Cox staining and Nissl staining were employed to detect the effect of sevoflurane inhalation in hippocampal neurons. Meanwhile, bioinformatics analysis was implemented, and western blot (WB) and bisulfite sequencing PCR (BSP) technique were utilized to validate this hypothesis. Moreover, the level of lipid peroxidation, mitochondrial membrane potential, morphology and membrane permeability, and cytoplasm calcium levels were investigated after Egr2 interference by using JC-1 probe, MitoTracker staining, Mitochondrial permeability transition pore (mPTP) assay, and Fluo calcium indicators, respectively. Additionally, Prussian blue staining was used to evaluate the iron content.Results: The behavioral tests indicated that the cognitive function was significantly attenuated after sevoflurane administration. The Golgi-Cox staining displayed that the dendritic length, density and nodes were significantly reduced, and the typical neuropathological changes including neuron loss, nucleus shrinkaged and disappearance of Nissl bodies were observed by Nissl staining. Moreover, bioinformatics analysis showed that the Egr2 expression was significantly upregulated, and WB and BSP confirmed this result. Additionally, the results suggested that sevoflurane administration elevated the cytoplasm calcium levels, reduced the mitochondrial membrane potential and triggered the opening of mPTP. Prussian blue staining showed that the iron deposition was apparently increased. However, Egr2 level downregulation partly reversed these above changes.Conclusion: These findings demonstrated that sevoflurane administration elicited mitochondrial dysfunction and iron dyshomeostasis, and eventually resulted in cognitive impairments, whereas suppressing Egr2 expression partly improved this pathological process.