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Abstract Type 2 diabetes mellitus (T2DM) and periodontitis (PD) have intricated connections as chronic inflammatory diseases. While the immune response is a key factor that accounts for their association, the underlying mechanisms remain unclear. To gain a deeper understanding of the connection, we conducted research using a multiomics approach. We generated whole genome and methylation profiling array data from the periodontium of PD patients with DM (PDDM) and without DM to confirm genetic and epigenetic changes. Independent bulk and single‐cell RNA sequencing data were employed to verify the expression levels of hypo‐methylated genes. We observed a gradual rise in C>T base substitutions and hypomethylation in PD and PDDM patients compared with healthy participants. Furthermore, specific genetic and epigenetic alterations were prominently associated with the Fc‐gamma receptor‐mediated phagocytosis pathway. The upregulation of these genes was confirmed in both the periodontal tissues of PD patients and the pancreatic tissues of T2DM patients. Through single‐cell RNA analysis of peripheral blood mononuclear cells, substantial upregulation of Fc‐gamma receptors and related genes was particularly identified in monocytes. Our findings suggest that targeting the Fc‐gamma signaling pathway in monocytes holds promise as a potential treatment strategy for managing systemic complications associated with diabetes.