Cellular senescence and inflammation-mediated phenotypic switch in smooth muscle cell (SMC) are pivotal factors in the development of aortic dissection. Chlorogenic acid (CGA), a polyphenolic compound of plant origin, exhibits remarkable anti-aging and anti-inflammation properties. However, the role of CGA in aortic dissection remains elusive. In this study, a β-aminopropionitrile (BAPN)-induced aortic dissection model in vivo and DOX-induced cell senescence model in vitro were employed, in combination with activity-based protein profiling (ABPP) technology, to explore the target by which CGA inhibits aortic dissection. The results revealed that CGA could prophylactically and therapeutically prevent BAPN-induced aortic dissection in mice. Transcriptome sequencing of aortic tissues demonstrated that CGA treatment downregulated the expression of genes related to senescence and synthesis, while upregulating the expression of contractile genes. These findings were further validated in DOX-induced senescent SMCs. Based on ABPP technology, a CGA chemical probe was utilized to explore its protein targets, and Mettl3 was identified and verified as a potential target of CGA in senescent SMCs. Our study offers novel insights into halting the progression of aortic dissection and may facilitate the application of CGA in the prevention of aortic dissection.