Background: Thoracic Aortic Aneurysm and Dissection (TAAD) is a life-threatening aortic disease defined by progressive medial degradation and vascular smooth muscle cell (VSMC) depletion. Current clinical management is limited to blood pressure control and surgical intervention, with no targeted pharmacological therapies available to halt disease progression. This study investigates the contribution of ferroptosis, an iron-dependent form of regulated cell death, to TAAD pathogenesis and its modulation by the ketogenic and kynurenine metabolic pathways. Methods: β-aminopropionitrile (BAPN)-induced and BAPN/Angiotensin II murine models of TAAD were used. Systemic metabolic intervention was conducted using ketone esters (KE), and cell-specific contributions were evaluated using global and Prrx1-specific IDO1 knockout models. Mechanistic studies in human aortic smooth muscle cells (HASMCs) utilized siRNA-mediated silencing (siGPX4, siNFE2L2), RSL3-induced ferroptotic stress, and metabolite rescue assays (β-OHB, 3-HAA). Findings were integrated with bioinformatic analyses of human TAAD transcriptomic datasets (GSE52093, GSE153434, GSE155468) to identify pathway-level vulnerabilities. Results: Ketone ester supplementation preserved aortic structural integrity, reducing TAAD incidence from 69% to 43% and increasing overall survival from 52% to 73%. Mechanistically, β-hydroxybutyrate (β-OHB) restored the Nrf2-GPX4/SLC7A11 antioxidant axis, neutralized the labile iron pool, and reversed pathological HO-1 over-activation. In parallel, bioinformatic and in vitro analyses identified a dysregulation in the kynurenine pathway in aneurysmal SMCs, defined by the profound downregulation of 3-hydroxyanthranilate 3,4-dioxygenase (HAAO). While 3-HAA rescued HASMCs from ferroptotic death, the loss of HAAO-mediated enzymatic continuity generates a context-dependent 3-HAA accumulation whose net role in the chronic aneurysmal environment warrants further investigation. Conclusion: These findings redefine TAAD as a structural-metabolic disease in which exhaustion of the cellular antioxidant program leads to medial depopulation. The ketogenic intervention represents a promising non-surgical prophylactic strategy, while the HAAO bottleneck and resultant 3-HAA accumulation emerge as candidate diagnostic biomarkers of aortic vulnerability. Restoring the metabolic resilience of the aortic media through Nrf2 activation or targeted kynurenine pathway modulation represents a new frontier in aortopathic prevention.