<p>Sjögren’s syndrome (SS) is a systemic autoimmune disorder driven by interactions among genetic susceptibility, environmental factors, and alterations in mucosal microbial ecosystems. Emerging evidence from studies of the gut, oral cavity, and ocular surface indicates that microbial dysbiosis is closely associated with SS. Patients frequently exhibit reduced beneficial commensals and expansion of potentially pathogenic taxa, accompanied by epithelial barrier disruption, imbalance of T helper 17 and regulatory T cells, abnormal B-cell responses, and sustained activation of type I interferon signaling. Several mechanisms may contribute to disease development, including molecular mimicry, exosome-mediated immune communication, and alterations in microbiota-derived metabolites. Integrated multi-omics approaches, particularly high-throughput sequencing and metabolomics, have revealed SS-associated microbial signatures and metabolic pathway changes, offering insights for biomarker discovery and therapeutic targeting. Microbiota-directed strategies, such as probiotic supplementation, fecal microbiota transplantation, and investigations of drug–microbiome interactions, have shown potential to restore immune homeostasis. However, current evidence remains limited by small cohort sizes, methodological heterogeneity, and insufficient clarification of causal relationships. This review summarizes microbial alterations in SS, their roles in immune dysregulation, and the therapeutic potential of microbiome-based interventions within the framework of personalized medicine.</p>