Early diagnosis of esophageal squamous cell carcinoma (ESCC) is crucial for improving patient prognosis. Currently, the diagnosis of ESCC primarily relies on endoscopic biopsy. Salivary exosomes have shown great potential in non-invasive screening, but their proteomic and lipidomic characteristics remain to be reported. Exosomes were isolated from salivary samples of 54 patients with ESCC and 62 healthy controls using ultracentrifugation, and subsequently subjected to non-targeted proteomic and lipidomic analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins and lipids in salivary exosomes were identified through differential analysis, and a comprehensive analysis of multi-omics data was performed using correlation analysis.