〔Abstract〕 Objective To explore the protection of ketogenic diet on hippocampal neuronal injury in mice exposure to high altitude hypoxia. Methods C57 BL/6 mice were randomly allocated into four groups: a normal oxygen control(NC) group, a normal oxygen with ketogenic diet(NK) group, a hypoxia control(HC) group, a hypoxia with ketogenic diet(HK) group(n=11). The hypobaric oxygen chamber was used to simulate high altitude(6 000 m)hypoxic environment, operating time 24 h/d, the control ratio of day to night approximately 12 h:12 h. HC group and HK group were given standard diet and ketogenic diet respectively for 3 weeks, and then were exposed to high-altitude hypoxia circumstances for 6 days. NC group and NK group were raised outside the hypobaric oxygen chamber after 3-week standard diet and ketogenic diet respectively. The pathological morphology of hippocampal neurons was examined by Nissl staining. Expressions of mitochondrial fusion protein 1(MFN1), mitochondrial fission protein 1(FIS1) were assayed by Western blot. Changes of mitochondrial oxygen consumption rate(OCR) in brain was detected by Seahorse energy metabolism analyzer. Results Compared with NC group, HC group showed the pathological damage such as decreased hippocampal neurons, widening intercellular spaces and nuclear pyknosis. Compared with HC group, HK group showed an increase of hippocampal neurons, a gradual alignment of cells and a decrease of nuclear pyknosis. The expression of FIS1 increased while MFN1 decreased in HC group compared with NC group. Compared with HC group, the expression of MFN1 increased while FIS1 decreased in HK group. Seahorse results showed that the mitochondrial OCR in brain of HC group decreased compared with NC group, which increased in HK group compared with HC group. Conclusion High altitude hypoxia causes damage of hippocampal neurons in mice. Ketogenic diet can improve the damage of hippocampal neurons in mice exposure to high altitude hypoxia.