INTRODUCTION: Aortic dissection (AD) is caused by inflammatory responses and extracellular matrix (ECM) degradation processes, in which S100A9, a proinflammatory protein, may play a role. This study explored the role S100A9/P38 MAPK/HSPB1 signaling axis in AD pathogenesis and the therapeutic potential of targeting this pathway. METHODS: S100A9 expression in the aortic tissues of patients with AD/healthy controls were analyzed using bioinformatics, ELISA, qPCR, western blotting, and immunohistochemistry. In an AD mouse model induced by β-aminopropionitrile and angiotensin II (Ang-II), S100A9 expression was inhibited using specific inhibitors to assess its relationship with AD, and proteomics were performed to explore the pathways related to S100A9 expression. Human aortic vascular smooth muscle cells (HVSMC) were treated with Ang-II, S100A9 knockdown, P38 MAPK inhibitors, and HSPB1 knockdown, and experimental methods were used to assess changes in inflammatory cytokines, ECM remodeling, cell proliferation, and apoptosis. Rescue experiments validated the role of the S100A9/P38 MAPK/HSPB1 axis. RESULTS: S100A9 was significantly upregulated in patients with AD, while levels of inflammatory cytokines and matrix metalloproteinases (MMPs) were elevated. S100a9 inhibition reduced the incidence of AD, improved survival, and stabilized the aortic structure in mice, with reduced collagen deposition and SMC apoptosis in vitro. S100A9 knockdown reduces Ang-II-induced HVSMC proliferation, apoptosis resistance, and ECM degradation. Mechanistic studies revealed that the S100A9/P38 MAPK/HSPB1 axis regulates inflammatory cytokine and MMPs release. CONCLUSION: S100A9 regulates inflammation and ECM degradation through the P38 MAPK/HSPB1 axis, influencing HVSMC proliferation and apoptosis and promoting AD development. This pathway may be a promising therapeutic target for AD treatment.