Progressive loss of vascular smooth muscle cells (VSMCs) is the pathophysiological basis for aortic aneurysm and dissection (AAD), a life-threatening disease, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and prevention of vascular remodeling-related diseases. In this study, we investigated the role of VSMC SIRT6 in AAD and the molecular mechanism. We showed that the expression levels of SIRT6 were significantly reduced in VSMCs of the thoracic aorta in AAD patients. We constructed a VSMC-specific Sirt6 deficient mouse line and found that loss of Sirt6 in VSMCs dramatically accelerated angiotensin II (Ang II)-induced AAD formation and rupture, even without an Apoe-deficient background. In human aortic smooth muscle cells (HASMCs), knockdown of SIRT6 led to mitochondrial dysfunction and accelerated VSMC senescence. We revealed that SIRT6 bound to and deacetylated NRF2, a key transcription factor for mitochondrial biogenesis. However, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex proteins. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang II-induced mitochondrial dysfunction in HASMCs. In a BAPN-induced TAAD mouse model, administration of MDL-811 (20 mg/kg, i.p., every other day for 28 d) effectively mitigated AAD progression and reduced mortality. These results suggest that SIRT6 plays a protective role against AAD development, and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.