Objective：To investigate the effect of 11β-hydroxysteroid dehydrogenase（11β-HSD1）gene knockout on the metabolism and cognitive function of mice. Methods：A total of 15 mice each in the C57BL/6J genetic background wild control group and 11β- HSD1 gene knockout group were fed with high fat for 20 weeks. We then assessed energy metabolism by metabolic cage，observed their cognitive function by behavioral evaluation，evaluated hippocampus mitochondria by electron microscope，and determined changes in cognitive function，mitochondrial function-related genes，and inflammatory genes by immunofluorescence and RT-PCR. Results：The 11β-HSD1 gene knockout in showed the enhanced learning and memory ability，increased grip strength，improved hippocampal microstructure，amplified mitochondrial content，up-regulated the genes related to cognition and mitochondrial respiratory function，and changed the inflammatory genes. Conclusion：Our study demonstrated that knockout 11β-HSD1 significantly improved cognitive function and grip strength mice fed high-fat diet，therefore may be an effective target for the treatment of cognitive dysfunction.