<p>Osteoporosis is a metabolic bone disease characterized by excessive osteoclast-mediated bone resorption. Stigmasterol glucoside (SG), a glycosylated phytosterol with enhanced hydrophilicity, has shown potential anti-inflammatory activities, but its role in bone metabolism remains largely unexplored. This study aimed to investigate the effects and underlying mechanisms of SG on osteoclastogenesis. An integrative pharmacological strategy was employed, combining network pharmacology and molecular docking to predict potential targets. These predictions were validated using primary bone marrow-derived macrophages (BMMs). Osteoclast differentiation and function were assessed via TRAcP staining, F-actin ring immunofluorescence, and bone resorption pit assays. Molecular mechanisms were elucidated using RT-qPCR, Western blotting, and luciferase reporter assays. Network pharmacology and molecular docking identified MAPK and STAT3 signaling axes as the core targets of SG, with high binding affinities for MAP2K1, JAK2, and STAT3. In vitro experiments demonstrated that SG dose-dependently inhibited RANKL-induced osteoclast differentiation and bone resorptive activity without cytotoxicity. At the molecular level, SG suppressed the expression and transcriptional activity of the master regulators NFATc1 and c-Fos, leading to the downregulation of essential functional markers. Further mechanistic investigations revealed that these inhibitory effects were driven by the attenuation of early-stage phosphorylation in the MAPK (p38, JNK, and ERK) and STAT3 signaling axes. SG effectively suppresses osteoclastogenesis and resorptive function by simultaneously intercepting the MAPK and STAT3/NFATc1 signaling axes. These findings provide experimental evidence that SG is a promising natural pharmacological candidate for the treatment of osteoporosis and bone loss-related disorders.</p>