Background and Purpose: Sevoflurane (Sev) is a commonly used anesthetic in clinic which can cause neurotoxicity. Postoperative cognitive dysfunction is a common clinical problem induced by some anesthetics such as Sev. However, the exact mechanism of neurotoxicity induced by Sev is unclear. Here we aimed to clarify a new mechanism of POCD induced by Sev. Experimental Approach: 15-month-old mice were treated with 2% Sev for 6 hours. Morris water maze (MWM) was used to evaluate the capacity of the mouse for spatial learning and memory. Major signalling profiles and the underlying mechanism of neurotoxicity or POCD was further explored by using the isobaric tags for relative and absolute quantitation, synchrotron radiation micro-X-ray fluorescence, the Seahorse XFe8 Extracellular Flux Analyzer, Western blot, RT-qPCR, and immunofluorescence assay. Key results: Sev caused POCD symptom through inducing iron accumulation and dysfunction of iron metabolism. Excessive iron increased ROS levels which further impaired mitochondrial function and led to glucose metabolism disorder and ATP decrease through regulating the expression of key enzyme genes or proteins including G6Pase, Pck1 and Cs. Meanwhile, Sev also inhibited the oxygen consumption rate and glucose absorption by down-regulating expression of glucose transporter 1 in cerebral vascular endothelial cells. The cross-dysfunction of iron and glucose metabolism caused the apoptosis in cortex and hippocampus through Bcl2/Bax pathway. Conclusions and implications: Sev caused apoptosis by cross-dysregulation of iron and glucose metabolism and induced energy stress in mice. Maintaining iron and glucose metabolism homeostasis maybe played an important role in cognitive impairment induced by Sev.