Aortic dissection (AD) is a rare but catastrophic disorder, and associated with significant morbidity among survivors. This study aimed to target IRE1 alpha-XBPls pathway pharmacologically, and evaluate its therapeutic potential in the occurrence and progression of AD. Western Blot and immunohistochemistry results showed that expression of XBPls was significantly increased in the human aorta samples of AD group in compared with the control group, and exclusively in aortic vascular smooth muscle cells (VSMCs). Further in vitro study revealed that Angiotensin II (Ang II) could increase the expression of XBPls and promote its nuclear translocation in cultured VSMCs, which leads to numerous gene transcription, including gp9lphox, Chop, Cleaved-caspase 3, Bax, and Bc1-2. These genes contribute to the production of reactive oxygen species (ROS), VMSCs phenotypic switch and apoptosis. Whereas an IRE1 alpha endoribonuclease domain inhibitor MKC-3946 could reverse it. Finally, the efficacy of MKC-3946 was tested in a mouse AD model. As shown in vitro, MKC-3946 could reduce the expression of XBPls and protect against AD by suppressing XBPls associated ROS production and apoptosis in VSMCs in vivo. The current study revealed the relevant role of IRE1 alpha-XBPls signaling pathway in AD occurrence and progression. MKC-3946 could be of great potential in clinical application.