Background <p>Periodontitis is a prevalent chronic inflammatory disease characterized by progressive destruction of periodontal tissues, driven by an exaggerated host immune response. Andrographolide, a bioactive compound extracted from Andrographis paniculata, has demonstrated significant anti-inflammatory potential in various disease models, yet its precise mechanisms of action in periodontitis remain unclear.</p> Methods <p>An integrated network pharmacology approach was employed to identify the intersecting targets of andrographolide and periodontitis, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein–protein interaction (PPI) network construction and topological analysis were conducted to identify hub genes, which were further evaluated through molecular docking. Finally, in vitro experiments using LPS-stimulated macrophages were performed to validate the anti-inflammatory effects of andrographolide via ELISA, RT-qPCR, and Western blotting.</p> Results <p>A total of 97 common targets were identified between andrographolide and periodontitis. Enrichment analyses revealed significant involvement in inflammatory and immune-related pathways, including the IL-17, TNF, Toll-like receptor, and NF-κB signaling pathways. Four hub genes (TP53, STAT3, NFKB1, and JUN) were identified as central nodes in the PPI network, and molecular docking confirmed favorable binding affinities with andrographolide. In vitro validation demonstrated that andrographolide significantly reduced LPS-induced production of pro-inflammatory cytokines (IL-6, IL-17, TNF-α, and MCP1) at both the transcriptional and protein levels in a dose-dependent manner.</p> Conclusion <p>This study elucidates the multi-target anti-inflammatory mechanisms of andrographolide in the context of periodontitis and highlights its potential as a promising therapeutic agent for modulating periodontal inflammation.</p>