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In a DSS\u2010induced colitis model, oral administration of kaempferol effectively alleviated characteristic symptoms of ulcerative colitis (UC) in mice. However, its regulatory effects on metabolism within the circulatory system, colon, and gut microenvironment remain insufficiently explored. Pharmacokinetic properties and metabolomics analysis revealed that the much higher level of kaempferol in the gut contents may contribute to its more pronounced metabolic regulatory effects on gut contents compared to those observed in the serum and colon. In detail, kaempferol significantly reversed 102 metabolites in gut contents, involving metabolic pathways comprising amino acid, bile acid, fatty acid, and nucleotide metabolism. Conversely, kaempferol modulated only 10 metabolites in serum and 17 in colon. The systemic effects of kaempferol mediated via gut\u2010host crosstalk were evidenced by the regulation of shared metabolic pathways. 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