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BACKGROUND AND OBJECTIVE To our knowledge, there is still a lack of scientific reports on the pharmacological mechanism of the Zuogui Pill (ZGP) for treating osteoporosis (OP). This study aimed to explore it via network pharmacology and molecular docking. METHODS We identified active compounds and associated targets in ZGP via two drug databases. Disease targets of OP were obtained utilizing five disease databases. Networks were established and analyzed through the Cytoscape software and STRING databases. Enrichment analyses were performed using the DAVID online tools. Molecular docking was performed using Maestro, PyMOL, and Discovery Studio software. RESULTS 89 drug active compounds, 365 drug targets, 2514 disease targets, and 163 drug-disease common targets were obtained. Quercetin, kaempferol, phenylalanine, isorhamnetin, betavulgarin, and glycitein may be the crucial compounds of ZGP in treating OP. AKT1, MAPK14, RELA, TNF, and JUN may be the most important therapeutic targets. Osteoclast differentiation, TNF, MAPK, and thyroid hormone signaling pathways may be the critical therapeutic signaling pathways. The potential therapeutic mechanism mainly relates to osteoblastic or osteoclastic differentiation, oxidative stress, and osteoclastic apoptosis. CONCLUSION This study has revealed the anti-OP mechanism of ZGP, which offers objective evidence for relevant clinical application and further basic research.