<p>This study investigated, for the first time, the salivary microbiome and metabolome profiles associated with dental caries in Tibetan children of mixed dentition residing in high-altitude areas. Moreover, a diagnostic model for caries was established by exploring the potential cariogenic mechanisms of identified biomarkers. Saliva samples were collected from 28 Tibetan children (aged 10.20 ± 0.67&#xa0;years in the high caries [HC] group, <i>n</i> = 15; 10.38 ± 0.65&#xa0;years in the caries-free [H] group, <i>n</i> = 13). Illumina 16S rRNA sequencing and untargeted liquid chromatography–mass spectrometry (LC–MS) were employed to analyze microbial composition and metabolic profiles, respectively. Although alpha diversity showed no significant differences among groups, beta diversity analysis revealed distinct microbial and metabolic differences between the HC and H groups. Several bacterial genera exhibited significant variations and were strongly correlated with caries status. Salivary microbial and metabolic compositions differed significantly between Tibetan children with and without caries in high-altitude areas; differential biomarkers may serve as diagnostic or early-warning indicators of dental caries in this unique population. The identified microorganisms and metabolites could be used as non-invasive biomarkers or early warning markers for dental caries detection in Tibetan children in high-altitude areas. Moreover, the further exploration of their pathogenic roles will be helpful for the prevention and discovery of therapeutic drug targets of caries in Tibetan children at high altitude.</p> Graphical abstract <p></p>