Periodontal disease, a prevalent oral inflammatory condition, is implicated in exacerbating systemic diseases. However, the molecular mechanisms underlying this association remain unclear. In this study, we performed RNA sequencing of gingival tissue samples collected from a mouse model of periodontal disease at multiple time points to investigate dynamic transcriptomic changes during disease progression. Our analysis revealed distinct temporal gene expression patterns associated with the key inflammatory and immune response pathways. These findings suggest stepwise molecular progression in the periodontal inflammatory process, potentially contributing to systemic inflammation through shared signaling networks. We further identified specific genes and pathways that may mediate the bidirectional relationship between periodontal disease and systemic conditions such as cardiovascular disease and diabetes. By elucidating the temporal dynamics of molecular changes in periodontal disease, this study provides insights into the pathogenesis and its systemic implications. It identifies potential biomarkers and therapeutic targets for local and systemic disease management.