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Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there is a lack of effective therapeutic drugs. There is great potential for natural products to be used in the development of anti-AD drugs. P-coumaric acid (PCA), a small molecule phenolic acid widely distributed in the plant kingdom, has pharmacological effects such as neuroprotection, but its anti-AD mechanism has not been fully elucidated. In the current study, we investigated the mechanism of PCA intervention in the Aβ 25-35- induced AD model using gut microbiomics and serum metabolomics combined with in vitro and in vivo pharmacological experiments. PCA was found to ameliorate cognitive dysfunction and neuronal cell damage in Aβ 25-35 -injected mice as measured by behavioral, pathological and biochemical indicators. 16S rDNA sequencing and serum metabolomics showed that PCA reduced the abundance of pro-inflammatory-associated microbiota (morganella, holdemanella, fusicatenibacter and serratia) in the gut, which were closely associated with metabolites of the glucose metabolism, arachidonic acid metabolism, tyrosine metabolism and phospholipid metabolism pathways in serum. Next, in vivo and in vitro pharmacological investigations revealed that PCA regulated Aβ 25-35 -induced disruption of glucose metabolism through activation of PI3K/AKT/Glut1 signaling. Additionally, PCA ameliorated Aβ 25-35 -induced neuroinflammation by inhibiting nuclear translocation of NF-κB and by modulating upstream MAPK signaling. In conclusion, PCA ameliorated cognitive deficits in Aβ 25-35 -induced AD mice by regulating glucose metabolism and neuroinflammation, and the mechanism is related not only to restoring homeostasis of gut microbiota and serum metabolites, but also to PI3K/AKT/Glut1 and MAPK/NF-κB signaling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)