BACKGROUND: Neurodegenerative disorders, such as Alzheimer's disease (AD), are characterized by a progressive decline in cognitive function. Modulating microglial metabolic reprogramming presents a promising therapeutic avenue for AD. Previous studies have shown that Zexie Tang (ZXT) possesses neuroprotective properties and can ameliorate cognitive impairment, but the underlying mechanisms remain unclear. PURPOSE: This study aimed to investigate the efficacy of ZXT in improving cognitive function in AD mice using a multi-omics approach and to explore its potential role in modulating microglial metabolic reprogramming. METHODS: Behavioral assessments were conducted to evaluate the effects of ZXT on cognitive function in APP/PS1 mice. H&E, Nissl, and Thioflavin S staining were performed to assess the impact of ZXT on brain pathology. A multi-omics approach, including transcriptomics, gut microbiota analysis, and metabolomics, was employed to elucidate the mechanisms of action of ZXT. RT-qPCR, immunoblotting, and immunofluorescence were used to validate the effects of ZXT on glycolipid metabolism, neuroinflammation, and the AMPK-mTOR-HIF1α pathway. RESULTS: ZXT effectively protected against cognitive deficits, reduced hippocampal neuronal apoptosis, and decreased Aβ plaque deposition. Transcriptomics analysis revealed that ZXT was involved in immune system processes and metabolic processes and had a specific cellular response with microglia. Additionally, ZXT regulated the composition and functions of brain metabolites and gut microbiota. Our study demonstrated that ZXT positively influenced glucolipid metabolism and attenuated neuroinflammation, which were linked to the AMPK-mTOR-HIF1α pathway in the brain. CONCLUSION: Our findings suggested that ZXT may mitigate cognitive deficits in APP/PS1 mice by modulating gut microbiota and enhancing brain energy metabolism. ZXT regulated glucolipid metabolism and neuroinflammation by modulating microglial metabolic reprogramming involving the AMPK-mTOR-HIF1α pathway.