Anchored in a network-toxicology framework and supported by multi-database target prediction, GEO transcriptomics, enrichment analyses, and molecular docking, this study delineates the molecular network linking nicotine to osteoporosis: among 388 nicotine-related targets and 1777 OP genes, 116 overlapped; PPI topology highlighted eight core nodes (SRC, BCL2, HIF1A, TNF, NFKB1, STAT3, ESR1, CASP3); enrichment underscored apoptosis and estrogen signaling as key pathways; and docking indicated favorable binding for several targets, with CASP3, ESR1, and SRC among the better binders. This evidence concerns the gene NFKB1 and osteoporosis.