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BACKGROUND Febrile seizures (FS) pose a severe threat to the neurological development of children. Probing the abnormality of host metabolism is essential for the prevention, diagnosis and treatment of FS. METHODS Based on the clinically collected serum and fecal samples, we used non-targeted metabolomics and 16S rDNA sequencing to explore the relationship of serum metabolite levels, gut microbiota community with the occurrence of FS. RESULTS Metabolomics analysis revealed the abnormalities in multiple metabolic pathways in serum of FS patients, such as tryptophan metabolism and steroid hormone biosynthesis. Intestinal flora analysis indicated that the α-diversity of gut microbiota in FS patients was significantly reduced. In addition, the relative abundances of a variety of bacteria at the phylum level were remarkably changed in patients with FS, including the decreased Firmicutes and Verrucomicrobia. Eleven serum metabolites were identified to be biomarker candidates for FS diagnosis. With the help of a panel biomarker strategy by combining four biomarkers as a cluster, four bacteria (i.e., Rothia, Coprococcus, Lactobacillus, and Oscillospira) in a defined panel displayed perfect differentiation of subtypes of FS. CONCLUSIONS Combining metabolomics and intestinal flora analysis revealed specific characteristics of children with FS, and provide new clues for the diagnosis of FS and the classification of seizure types. In summary, these findings may provide new insights into revealing the significance of serum metabolites and gut microbiota in the pathogenesis of FS.