Objective To investigate the molecular mechanism underlying the intervention of?Lycium barbarum L. (LB) in diabetic periodontitis (DP).Methods?A DP rat model was established via intraperitoneal injection of streptozotocin (STZ) combined with a high-fat diet (60% fat). Maxillae were harvested, decalcified, embedded, sectioned, and subjected to hematoxylin-eosin (HE) staining to assess pathological changes in periodontal tissues. Active components of LB and their potential targets were screened using the TCMSP and BATMAN-TCM databases. Disease targets associated with DP were retrieved from databases including OMIM and GeneCards. Common targets shared between LB and DP were identified through Venn diagram analysis. A protein-protein interaction (PPI) network was constructed using the STRING database (confidence score ≥ 0.9, hiding disconnected nodes), and its topological properties were analyzed using Cytoscape software to identify hub targets. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID platform. Molecular docking validation was conducted using AutoDock Vina.?In vitro experiments were performed to determine the safe concentration of?Lycium barbarum?extract (2.0 mg/mL) using the CCK-8 assay and to evaluate its effects on human umbilical vein endothelial cell (HUVEC) migration, macrophage inflammatory cytokine expression, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) under a diabetic microenvironment through scratch wound healing assays, quantitative real-time PCR (qPCR), alkaline phosphatase (ALP) staining, alizarin red S (ARS) staining, and osteogenic gene expression analysis.Results?Animal experiments demonstrated that LB extract significantly ameliorated periodontal inflammation in DP rats. Network pharmacology analysis identified 36 active components of LB (e.g., quercetin, β-sitosterol) and 60 common targets. Hub targets included AKT1, IL6, and TNF. KEGG pathway analysis indicated that these targets were primarily enriched in pathways such as AGE-RAGE signaling pathway in diabetic complications, Diabetic cardiomyopathy, and Fluid shear stress and atherosclerosis. Molecular docking results revealed favorable binding activity between active components (e.g., quercetin) and the core targets (AKT1, IL6, TNF).The CCK-8 assay showed?Lycium barbarum?extract (0.5–2.5 mg/mL) significantly enhanced cell proliferation, leading to selection of 2.0 mg/mL for further study.?In vitro?experiments demonstrated the extract: reversed AGEs-induced HUVEC migration inhibition; downregulated macrophage pro-inflammatory cytokines (Tnf,?Il6) while upregulating?Il10; and counteracted AGEs-mediated suppression of BMSC osteogenic differentiation, evidenced by enhanced ALP/ARS staining and elevated osteogenic gene expression (Alp,?Runx2,?Bglap).Conclusion Lycium barbarum L. may promote the repair of diabetic periodontal bone defects potentially by inhibiting the AGE-RAGE signaling pathway, thereby reducing the release of downstream inflammatory cytokines, while synergistically improving vascular function and osteogenic differentiation.