Objective To investigate the role of S100 calcium binding protein A11 (S100A11) in aortic dissection (AD) and its possible mechanism. Methods In vivo, lentivirus plasmid Lv-S100A11-shRNA and negative control plasmid Lv-NC-shRNA were constructed and transfected into HEK293T cells respectively to obtain viral supernatant. Forty SD rats were randomly divided into 5 groups:control group (without any intervention), sham operation group (with physiological saline injected into the tail vein), AD group (with 0.25% β-aminopropionitrile added into drinking water for 3 consecutive weeks to establish AD model), AD+Lv-NC-shRNA group (AD model rats were injected with Lv-NC-shRNA via tail vein) and AD+Lv-S100A11-shRNA group (AD model rats were injected with Lv-S100A11-shRNA via tail vein), with 8 rats in each group. Hematoxylin-eosin (H-E) staining was used to observe the histopathological changes of the aorta, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining was used to observe cell apoptosis, immunohistochemistry staining was used to detect the protein expression levels of S100A11 and downstream signaling pathway related proteins receptor for advanced glycation endproducts (RAGE) and phosphorylated p38 (p-p38), and Western blotting was used to detect the protein expression levels of migration proteins matrix metalloproteinase (MMP) 2 and MMP9, apoptosis proteins B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X (Bax), proliferation proteins proliferating cell nuclear antigen (PCNA) and Ki-67. In vitro, the S100A11 overexpression plasmid OV-S100A11 was constructed, and human aortic smooth muscle cells (HASMC) were divided into 3 groups:control group (without any intervention), EV group (transfected with pIRES2-GFP empty vector) and OV-S100A11 group (transfected with pIRES2-GFP-S100A11 overexpression S100A11). Flow cytometry was used to detect apoptosis, and then the cells transfected with pIRES2-GFP-S100A11 were treated with RAGE inhibitor FPS ZM1 and p38 phosphorylation inhibitor SB203580. Western blotting was used to detect the protein expression of S100A11, RAGE, p38, p-p38, MMP2, MMP9, Bax, Bcl-2, PCNA and Ki-67. Results The results of animal experiments showed that compared with the sham operation group, the aortic vessels of rats in the AD group formed a blood-filled dissection, the apoptotic cells were increased, the protein levels of S100A11, RAGE, p-p38, MMP2, MMP9 and Bax were increased (all P<0.01), while the protein levels of Bcl-2, PCNA and Ki-67 were decreased (all P<0.01). Compared with the AD group, the aortic lesions in the Lv-S100A11-shRNA group were relieved, the apoptotic cells were decreased, the levels of S100A11, RAGE, p-p38, MMP2, MMP9 and Bax were decreased (all P<0.01), while the protein levels of Bcl-2, PCNA and Ki-67 were increased (all P<0.01). The results of cell experiments showed that the apoptosis rate of OV-S100A11 group was increased compared with the control group (all P<0.01), the protein levels of RAGE, p-p38, MMP2, MMP9 and Bax in the cells were increased (all P<0.01), the protein levels of Bcl-2, PCNA and Ki-67 were decreased (all P<0.01), but the change of the above proteins was reversed after the treatment with FPS ZM1 and SB203580. Conclusion S100A11 is highly expressed in AD formation rats, and it can promote cell apoptosis through RAGE-p38 mitogen activated protein kinase pathway, participating in AD formation.