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Osteoporosis is a systemic skeletal disease that can easily lead to bone fractures. Berberine has been shown to be effective in treating osteoporosis. This study was conducted to identify the potential mechanism of berberine in treating this complaint. We screened potential targets of berberine and identified the osteoporosis-related differentially expressed genes (DEGs) in the microarray dataset GSE56815. Protein–protein interaction (PPI) network construction, hub targets identification, and pathway enrichment were carried out to find the potential targets. Molecular docking and molecular dynamics studies were performed to verify the combination of berberine with its treatment-related central targets. In addition, SwissADME preliminarily evaluated the physicochemical properties of berberine. Through data mining, 23 osteoporosis-related targets of berberine were selected. PPI and module analyses suggested that AKT1, MAPK1, ESR1, AR, TP53, and PTGS2 are the core targets of berberine. Docking and molecular dynamics studies showed that berberine could stably bind to core proteins to form a protein–ligand complex. The enrichment analysis showed that the estrogen signaling pathway and thyroid hormone signaling pathway play important roles in curing osteoporosis. To sum up, berberine primarily acts on AKT1, MAPK1, ESR1, AR, TP53, and PTGS2, mainly regulating the estrogen and thyroid hormone signaling pathways to treat osteoporosis in a multi-target, multi-pathway, and multi-system manner.