〔Abstract〕 Objective To explore the potential mechanisms by which Myristica fragrans prevents and treats atherosclerosis (AS). Methods The major active components of Myristica fragrans and their shared targets with AS were obtained from databases. The shared targets were subjected to pathway enrichment analysis and PPI network construction using the ClusterProfile package and the STRING database. Molecular docking between key targets and major active components was performed using AutoDock. Gene expression data from early and late, as well as stable and unstable AS plaques, were used to validate changes of key targets and major pathways during AS progression. Western blot, flow cytometry, YO-PRO-1/PI staining, and TUNEL staining were applied to verify the main mechanisms.Results Nine active components of Myristica fragrans interacted with 293 AS-related targets, among which eight components acted on an average of 57.0% of the shared targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that the anti-AS effects mainly involved oxidative stress, inflammation, lipid metabolism, fluid shear stress, and apoptosis pathways. PPI network revealed JUN, CASP3,MAPK3, and AKT1 as key targets mainly involved in regulating apoptosis. Molecular docking showed stable binding conformations and high affinities between major components and these targets. Integrated analysis of gene expression in early and late, as well as stable and unstable AS plaques, showed significant enrichment of leukocyte apoptosis pathways in late and unstable plaques. Cell experiments further confirmed that Myristica fragrans significantly reduced Cleaved-CASP3（P=0 .04）and p-MAPK3（P=0 .0003）levels,increased p-AKT1（P=0 .004）levels,and inhibited macrophage apoptosis. Conclusion Myristica fragrans potentially interferes with AS development by modulating pathways related to oxidative stress, inflammation, lipid metabolism, fluid shear stress, and apoptosis, with CASP3 , MAPK3 , and AKT1 serving as key targets mediating its anti-apoptotic and anti-AS effects.