BACKGROUND Metabolomics is the study of metabolome which describes the full repertoire of small molecules, and the analysis of salivary metabolomics may help in identifying tumor-specific biomarkers for early diagnosis and prediction of tumor progression. The aim of the study was to evaluate the clinical utility of salivary metabolites in oral leukoplakia and oral squamous cell carcinoma. METHODS Salivary metabolomic profile of patients diagnosed with oral leukoplakia (n = 21) and oral squamous cell carcinoma (n = 22) was compared with apparently normal controls (n = 18) using Q-TOF-liquid chromatography-mass spectrometry. MassHunter profile software and Metlin database were used for metabolite identification. ANOVA to identify the regulation of metabolites between the three groups, t test (P < 0.05) to signify the changes between two groups, and chi-square test (P < 0.05) to indicate the presence or absence of metabolites in the study participants of the three groups were performed. RESULTS Significant upregulation of 1-methylhistidine, inositol 1,3,4-triphosphate, d-glycerate-2-phosphate, 4-nitroquinoline-1-oxide, 2-oxoarginine, norcocaine nitroxide, sphinganine-1-phosphate, and pseudouridine in oral leukoplakia and OSCC was noted. Downregulated compounds in the diseased groups included l-homocysteic acid, ubiquinone, neuraminic acid, and estradiol valerate. CONCLUSIONS A range of salivary metabolites were significantly altered in oral leukoplakia and oral squamous cell carcinoma. Further, it is necessary to evaluate the clinical utility of the individual metabolites in preventing malignant transformation of oral leukoplakia and to improve prognosis of oral squamous cell carcinoma.