<p>Chinese yam, a plant used in traditional medicine and food, shows promise for treating osteoporosis, but its exact mechanism of action remains unclear. In this study, employs network pharmacology, molecular dynamics simulation techniques, and in vitro and in vivo experiments were employed to investigate the potential mechanisms underlying the therapeutic effects of Chinese yam on osteoporosis. Our study indicates that Chinese yam primarily exerts its effects primarily through several of its active components including Phytocassane A, Batatasin II, Gibberellin, Dihydroquercetin, Garcinone D, and Diosgenin. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that the PI3K/Akt signaling pathway and MAPK signaling pathway were enriched with multiple targets, including EGFR, SRC, IL-6, AKT1, and CTNNB1. The results from molecular docking and molecular dynamics simulations revealed favourable binding stability of the target–compound complexes. Among them, Dihydroquercetin and Garcinone D demonstrated superior binding affinity for each target. In a zebrafish model demonstrated that Chinese yam extract effectively alleviated dexamethasone-induced inhibition of bone mineralization. We also found that Chinese yam extract increased alkaline phosphatase (ALP) activity, upregulated the protein expression of runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN), and promoted PI3K phosphorylation in MC3T3-E1 cells treated with dexamethasone, and these effects could be reversed by a PI3K inhibitor (LY294002). This study revealed the active components and mechanisms underlying the efficacy of Chinese yam in treating osteoporosis, providing a theoretical foundation and research data for its clinical application in osteoporosis therapy.</p>