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Endothelial cells (ECs) sense hemodynamic forces and critically influence aortic aneurysm and dissection (AAD) development. However, the possible contribution of the mechanical sensor Piezo1 to AAD remains elusive. Single-cell mRNA sequencing identified Piezo1 as the most up-regulated mechanical sensor in ECs from AAD model mice. Immunofluorescence and immunoblotting confirmed markedly increased Piezo1 protein in human and mouse AAD samples. Disturbed flow induced by abdominal aortic constriction plus Angiotensin II up-regulated Piezo1 expression and AAD incidence, whereas Piezo1 inhibition attenuated both. Moreover, EC-specific Piezo1 deficiency was sufficient to suppress β-aminopropionitrile- and Ang II-induced AAD formation in mice. Mechanistically, we discovered the disturbed shear stress-induced opening of the endothelial barrier via Piezo1 and subsequent Ca²⁺/MLC/PYK2/SRC-mediated activation of downstream signaling. In addition, in an Ang II-induced endothelial barrier dysfunction model, Piezo1 deficiency in ECs ameliorated Ang II-induced barrier dysfunction. Further study revealed that Piezo1 activation in ECs promoted the up-regulation of CCL2 in a STAT3-dependent manner and strongly promoted the chemotactic recruitment of monocytes/macrophages to the aorta. Importantly, blocking CCR2 reduced monocyte/macrophage recruitment and subsequently attenuated Piezo1 up-regulation-aggravated AAD formation. Transcriptome analysis of human AAD samples revealed a positive correlation between Piezo1 and inflammation of the aorta. We demonstrate that Piezo1 directly links mechanical sensing under disturbed flow to a pathogenic cascade of endothelial barrier dysfunction and inflammatory cell recruitment. Consequently, interventions targeting Piezo1 or the downstream STAT3-CCL2/CCR2 signaling hold therapeutic promise for AAD.