Loss-of-function mutations in NOTCH1 were previously linked to thoracic aortopathy, a condition for which non-surgical treatment options are limited. Based on clinical proteome analysis, we hypothesized that mitochondrial fusion and biogenesis in aortic smooth muscle cells (SMCs) are crucial for regulating the progression of NOTCH1-related aortopathy. Here we demonstrate that SMC-specific Notch1 knockout mice develop aortic pathology, including stiffening, dilation and focal dissection. These changes are accompanied by decreased expression of MFN1/2 and TFAM, mirroring findings in human patients. SMC-specific deletion of Mfn1 and/or Mfn2 genes recapitulates the aortopathy seen in Notch1-deficient mice. Prophylactic or therapeutic approaches aimed at increasing mitochondrial DNA copy number, either through AAV-mediated overexpression of Mfn1/2 or oral treatment with mitofusion activators teriflunomide or leflunomide, help mitigate or slow the progression of aortopathy in SMC-Notch1