This study aimed to explore the molecular mechanisms underlying the therapeutic effects of Qihuang JianPi ZiShen granule (QJZG) in treating Sjögren's syndrome (SS) using a combination of network pharmacology, transcriptomics, and experimental validation. We conducted differential expression analysis, weighted gene co-expression network analysis, and utilized GeneCards along with other databases to identify potential therapeutic targets for SS. Concurrently, the active ingredients of QJZG and their associated targets were extracted from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Network pharmacology was then employed to predict the therapeutic targets and biological pathways through which QJZG may exert its effects on SS. To validate these predictions, we performed immune infiltration analysis and molecular docking studies, followed by transcriptomic sequencing and in vitro experiments for further confirmation. A total of 1,570 SS-related targets were identified, along with 70 active ingredients of QJZG and 253 associated targets, 99 of which overlapped with the SS-related targets. Protein-protein interaction network analysis revealed hub targets, including IL-1β, TNF, and IL-6. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis highlighted significant pathways such as the "TNF signaling pathway" and "Apoptosis". Immune infiltration analysis suggested that IL-1β, TNF, and IL-6 play critical roles in the pathogenesis and progression of SS. Molecular docking studies demonstrated strong binding affinities between the core ingredients of QJZG and hub targets. Transcriptomic sequencing confirmed that QJZG modulates SS through the TNF signaling pathway. In vitro experiments showed that QJZG, at a concentration of 4 mg/mL, exerted the most pronounced effects on human salivary gland (HSG) cells. Furthermore, treatment of interferon-γ-induced HSG cells with QJZG led to varying degrees of recovery in both inflammatory and apoptotic processes. Real-time quantitative PCR (RT-qPCR) and Western blot analyses further revealed that QJZG influences SS by modulating the expression of IL-1β, TNF-α, IL-6, and apoptotic-related cytokines. The results suggest that the therapeutic effects of QJZG in treating SS may be mediated through the TNF signaling and apoptosis pathways. This is likely achieved by downregulating pro-inflammatory factors such as IL-1β, TNF-α, and IL-6, which in turn alleviates inflammation-induced damage to the salivary glands.