Aortic dissection (AD) is a devastating disease with rapid progression and high mortality, and hypertension is a leading cause for AD. The aim of this study was to compare the protein expression profiles of aortas from patients with and without AD, screen vital proteins and explore their potential roles to grasp a further understanding of the pathogenesis mechanism of AD. The results of Tandem Mass Tag (TMT) sequencing revealed the different protein expression profiles between AD and control groups. 131 proteins were significantly upregulated and 239 proteins were prominently downregulated in AD. Upon further enrichment analysis of differential proteins, we found that 5 signaling pathways changed significantly in AD such as glycolysis, ECM and the other three pathways. Moreover, PPI networks were constructed to locate nodal proteins that may be essential points for AD. Our observation demonstrates for the first time that the protein expression in AD was notably changed compared to the control. Our results present evidences that glycolysis and ECM signaling pathway may present a promising approach for the etiology of AD.