Zingerone (Zin) exhibits multiple pharmacological properties, including anti-inflammatory, immunomodulatory, anxiolytic, anti-thrombotic, radioprotective, and antimicrobial activities. However, the therapeutic potential of Zin in coronary artery atherosclerotic heart disease (CHD) remains unexplored. This study aims to elucidate the role and underlying molecular mechanisms of Zin in CHD treatment. Putative Zin targets associated with CHD were identified through online database screening followed by functional enrichment analysis. Core target genes were screened using Protein-protein interaction (PPI) Network analysis, machine learning algorithms, molecular docking, and molecular dynamics simulations. Protein expression was examined using western blot. The levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were detected using detection kits. The senescence of cells was analyzed using senescence-associated β-galactosidase (SA-β-gal) staining kits. Zin was predicted to target several core genes, including v-akt murine thymoma viral oncogene homolog 2 (AKT2), heat shock protein 90α family class B member 1 (HSP90AB1), nuclear receptor subfamily 3 group C member 1 (NR3C1), forkhead box O1 (FOXO1), and toll-like receptor 4 (TLR4), potentially contributing to the alleviation of CHD. Furthermore, molecular docking and molecular dynamics simulation predicted a stable binding interaction between Zin and HSP90AB1. Zin ameliorated ox-LDL-stimulated inflammation, an effect that was associated with downregulation of HSP90AB1. Furthermore, Zin alleviated ox-LDL-induced senescence and apoptosis in a manner correlated with reduced HSP90AB1 levels in vitro. Zin suppresses inflammation, senescence, and apoptosis of oxidized low-density lipoprotein-induced primary human coronary artery endothelial cells in a manner associated with HSP90AB1 silencing. These findings provide a foundation for the further development of Zin-based treatment strategies for CHD.