Objective To investigate the protective effects and potential mechanisms of tetrahydrocurcumin (THC) on thoracic aortic aneurysm and dissection (TAAD) in mice. Methods The mouse model of TAAD was induced in 3-week-old C57BL/6 mice with β-aminopropionitrile (BAPN) administration (orally, diluted in drinking water, 1 g/kg/day). Eighty mice were randomly divided into Con group, BAPN+V group, BAPN+THC group and BAPN+THC+3-TYP group, with 20 mice in each group. After 4 weeks, the survival rate of mice in each group was recorded. The maximum diameter of mouse aorta was measured, HE and EVG staining were used to evaluate the histomorphology and aortic wall elastin integrity. Immunohistochemical staining was used to observe macrophage infiltration. Immunofluorescence staining was used to assess the expression of α-SMA and OPN. The production of reactive oxygen species (ROS) was measured using DHE staining. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were determined by special kits. Protein expressions MMP2, MMP9, IL-6, TNF-α, NRF2, NOX2, α-SMA, OPN, SIRT3, Ac-SOD2 and SOD2 were measured by western blotting. Results Compared with the BAPN group, mice in the BAPN+THC group showed significantly higher survival rate and lower incidence rate, the degree of aortic dilatation and morphology and structure were largely improved (P < 0.05); Infiltration of CD68-positive macrophages, MMP2, MMP9, IL-6, and TNF-α expressions were remarkably lower (P < 0.05); ROS generation, MDA content, and NOX2 expression in aortic tissue were significantly decreased, while SOD activity and NRF2 expression were greatly higher (P < 0.05); α-SMA expression was remarkably increased, while OPN expression was far lower (P < 0.05); protein expression of SIRT3 was far higher, while the Ac-SOD2/SOD2 ratio was remarkably lower (P < 0.01); After treatment with the SIRT3-specific inhibitor and silencing of SIRT3, the ability of THC to resist TAAD through the SIRT3 signaling pathway was counteracted (all P<0.05). Conclusions THC alleviated the inflammation and oxidative stress in aortic tissues by activating the SIRT3 signaling pathway, thus inhibiting the phenotypic transformation of vascular smooth muscle cells (VSMC) and resisting the formation of TAAD in mice.