[Abstract] Objective: To investigate the effect of 11β-hydroxysteroid dehydrogenase (11β-hydroxysteroid dehydrogenase, 11β-HSD1) gene knockout on the metabolism and cognitive function of mice. Methods: 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: 11β-HSD1 knockout mice showed 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 gene significantly improved cognitive function and grip strength in high-fat diet-induced obese mice, therefore 11β-HSD1 may be an effective target for the treatment of cognitive dysfunction.