Hyperlipidemia has been implicated in the progression of periodontitis, yet the molecular mechanisms linking lipid dysregulation to periodontal inflammation remain incompletely understood. This study investigated the therapeutic potential of RYR extract using integrated network pharmacology, in vitro, and in vivo approaches. In human periodontal ligament cells, combined stimulation with Porphyromonas gingivalis LPS (Pg-LPS) and cholesterol induced excessive endoplasmic reticulum (ER) stress and was accompanied by the transcriptional repression of liver X receptor alpha (LXRα), in contrast to the compensatory upregulation observed under single-stimulus conditions. These changes were associated with intracellular cholesterol accumulation and amplified inflammatory responses. RYR extract attenuated ER stress and reactive oxygen species production while restoring LXRα and ABCA1 expression, leading to improved cholesterol homeostasis and significant suppression of pro-inflammatory mediators. In a Pg-LPS-induced rat model of periodontitis, oral administration of RYR reduced alveolar bone loss and periodontal inflammation. Collectively, these findings suggest that RYR mitigates hyperlipidemia-associated periodontal inflammation by modulating ER stress and LXRα-related cholesterol regulatory pathways, highlighting its potential as a complementary therapeutic strategy for periodontitis in the context of metabolic disorders.