Symptomatic irreversible pulpitis (SIP) is a painful dental condition often diagnosed based on subjective pain reports, which are frequently vague and poorly localized, leading to diagnostic uncertainty and potential overtreatment. To overcome this, our study integrates multiomics data to identify objective molecular signatures of pulp inflammation and pain modulation, offering new avenues for precise, biologically informed diagnosis. Methods: Proteomic profiling of symptomatic irreversible pulpitis (SIP) and healthy pulp tissues (SIP, n=10; healthy, n=5) was conducted via iTRAQ-labeled liquid chromatography-tandem mass spectrometry (iTRAQ-LC-MS). Their transcriptional expression was examined in two independent GEO datasets (GSE77459 and GSE92681) to determine consistency across omics levels. Cross-platform integration of differentially expressed proteins (DEPs) and differentially expressed genes (DEGs) was performed to identify consistently upregulated candidates. Furthermore, single-cell RNA sequencing data (GSE185222) were analyzed to delineate the cell-type-specific expression profiles of key molecules. Protein expression was further validated by Western blotting. To evaluate non-invasive diagnostic potential, salivary concentrations of selected markers were quantified using enzyme-linked immunosorbent assays (ELISA). Group differences were assessed statistically (p < 0.05), and diagnostic performance was evaluated using Receiver Operating Characteristic (ROC) analysis. Results: Proteomic profiling identified 5057 proteins, while transcriptomic analysis revealed 18,777 genes. Enrichment analyses highlighted activation of leukocyte-mediated immunity responses and pathways related to nociception. Cross-platform integration identified six consistently upregulated molecules: matrix metalloproteinase 9 (MMP9), neutrophil cytosolic factor 2 (NCF2), nuclear factor kappa-B1 (NF-κB1), calcium/calmodulin-dependent protein kinase1 (CAMK1), TNF receptor–associated factor1 (TRAF1), and nucleus accumbens-associated 1 (NACC1). Single-cell transcriptomic analysis demonstrated distinct cell-type-specific expression across macrophages, osteoblast-lineage cells, fibroblasts, and dental pulp stem cells. Western blot validation (SIP, n=25; healthy, n=25) was performed with random sample allocation, blinded quantification, and triplicate technical repeats. Finally, salivary ELISA (n=48) demonstrated that NF-κB1, TRAF1, and NACC1 were significantly elevated in SIP, with high diagnostic accuracy. The combined model of TRAF1+ NF-κB1 achieved an AUC of 0.988. Conclusions: These findings highlight key inflammatory mediators and propose a feasible non-invasive biomarker panel for SIP diagnosis.