<p>Lipid metabolism imbalance and inflammation are important mechanisms driving osteoporosis. Gushudan (GSD) has the effect of tonifying the kidney and strengthening bones. However, the preventive mechanism of GSD against postmenopausal osteoporosis (PMOP) by modulating lipid metabolism remains to be further elucidated. A multi-omics strategy integrating lipidomics, transcriptomics, network pharmacology, and molecular docking was developed to investigate the potential mechanistic targets and pharmacodynamic material basis of GSD in preventing PMOP. Firstly, lipidomics analysis employing the dual-MS platform of UHPLC-Q-Orbitrap HRMS and UHPLC-MS/MS demonstrated that GSD improved the disorder of the lipid-inflammatory crosstalk mechanism involving glycerophospholipids and arachidonic acid in PMOP rats. Secondly, the combined analysis of lipidomics and network pharmacology predicted that <i>Pla2g2a</i> might be a potential mechanistic target linking lipid metabolism disorder to PMOP. Furthermore, high-throughput RNA sequencing transcriptomics was conducted to reveal that GSD significantly regulated 49 differentially expressed genes in PMOP rats, with the reversed genes (represented by <i>Pla2g2a</i>) markedly enriched in the arachidonic acid metabolism pathway. Finally, molecular docking was used to screen four active ingredients: przewaquinone A, naringenin, salvianolic acid D, and tricin, which were found to target <i>Pla2g2a</i>. In conclusion, this work achieved multi-dimensional cross-analysis by integrating multiple approaches, suggesting that GSD might ameliorate the lipid-inflammatory crosstalk disorder in PMOP rats by downregulating <i>Pla2g2a</i> expression, thereby restoring bone homeostasis. These findings provide new research clues and a potential target basis for the mechanistic investigation of PMOP.</p> Graphical Abstract <p></p>