Primary Sjögren's disease (SjD) is a slow-progressing autoimmune disease that affects salivary and lacrimal glands, causing dry eyes (xerophthalmia) and dry mouth (xerostomia). Diagnosing SjD involves clinical, serological, and histological assessments, but reliable biomarkers are lacking. This study analysed the metabolic and proteomic profiles of 19 female SjD patients (based on ACR-EULAR criteria) compared to 20 healthy individuals. Saliva and blood samples were analysed using mass spectrometry and chromatography. Proteomic analysis was performed with the nanoElute nanoflow system coupled to a timsTof-Pro mass spectrometer, and metabolic profiling with a GC-TOF/MS Pegasus HT. Statistical tests identified significant differences in metabolites and proteins between SjD patients and controls. Metabolome analysis revealed changes in amino acid synthesis, purine and lipid metabolism, and exposure to external compounds. Proteomic analysis indicated immune-related proteins and inflammatory lipid metabolism. GNAI2, B2MG, NGAL, SLUR2, HS90, SODC, and A2GL emerged as potential biomarkers for SjD. This study demonstrates the potential of high-performance techniques in identifying biomarkers for SjD diagnosis and prognosis.