BACKGROUND: Periodontitis, a chronic infectious disease, presents significant treatment challenges due to antibiotic resistance and high recurrence rates, necessitating novel therapeutics. METHODS: Network pharmacology identified ISL's potential targets in periodontitis, focusing on NF-κB signaling pathway. Toxicity was assessed via MTT assay and long-term toxicity studies in vivo. Anti-inflammatory effects were evaluated using enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), while antibacterial activity was tested in vivo. Micro-computed Tomography (Micro-CT) and hematoxylin and eosin (H&E) staining analyzed periodontal tissue recovery. Western blotting measured NF-κB-p65 and IκB phosphorylation. Molecular docking and dynamics simulations explored ISL's targets. RESULTS: ISL exhibited low toxicity and reduced IL-6, IL-1β, and TNF-α levels in vitro and in vivo. It demonstrated strong antibacterial effects and mitigated alveolar bone loss. Phosphorylation of NF-κB-p65 and IκB decreased in immune cells, with IKKB (-8.4 docking score) identified as a stable target. CONCLUSION: ISL effectively treats periodontitis by combining antibacterial and anti-inflammatory actions, targeting IKKB to suppress NF-κB signaling pathway. This study highlights ISL's therapeutic potential and provides a foundation for developing periodontitis treatments.