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Simple Summary Fear extinction is the driving mechanism to reduce the fear response, and it is the basis of exposure-based cognitive-behavioral therapy. Butyrylcholinesterase (BChE) seems to be involved in regulating cognitive function, and its relationship with fear extinction memory has not been reported. BChE knockout mice and wild-type mice with administration of (R)-bambuterol, a BChE inhibitor, were used in this study. In addition to immunohistochemistry and metabolite analysis using mass spectrometry imaging, the influence of age on the conditioned fear test, Morris water maze experiment, and open field test were carefully evaluated. Our results showed that BChE inhibition accelerates the fear extinction memory in mice and delays the cognitive decline in the early stages of aging. Abstract Butyrylcholinesterase (BChE) is detected in plaques preferentially in Alzheimer’s disease (AD) and may be associated with stress disorders. However, the physiological function of BChE in the central nervous system remains to be further investigated. BChE knockout (KO) mice and wild-type (WT) mice with orally or intranasal administration of (R)-bambuterol were used to explore the effect of BChE on behavior changes. (R)-bambuterol is a specific and reversible inhibitor of BChE. The behavior changes were evaluated and compared among 3–10 month old mice. Our finding showed that BChE KO and (R)-bambuterol administration enhanced episodic memory, including fear conditioning memory and fear extinction memory in fear conditioning and fear extinction test. BChE KO and (R)-bambuterol administered mice rescued age-related spatial memory and general activity in the water maze test and open field test. The brain metabolomics were imaged using a desorption electrospray ionization mass spectrometry imaging (DESI-MSI). The image of DESI-MS demonstrated that glutamine content increased in the brain of BChE KO mice. In conclusion, this study found that inhibition of BChE ameliorated episodic and spatial memories. This study also suggested that (R)-bambuterol as a BChE inhibitor has the potential application in the treatment of post-traumatic stress disorder (PTSD) and early cognitive decline.