Hypertension-induced arterial stiffness contributes to both reduced vascular and cardiac function. While the pathophysiology of aortic stiffness is not completely understood, significant vascular remodeling occurs in response to stimuli such as vascular stress and Ang II. The goal of this study was to determine whether a polyphenol-enriched muscadine grape skin and seed extract (MGE) improves Ang II-induced aortic remodeling. Sprague-Dawley rats (male, 8 weeks old) received normal drinking water (Control), 0.2 mg total phenolics/mL in their drinking water (MGE), 24 μg/kg/h of Ang II via osmotic minipump (Ang II), or both Ang II and MGE (Ang II/MGE, pre-treated with MGE for 1 week prior to Ang II treatment). MGE had no effect on systolic blood pressure, measured by tail cuff plethysmography, in normotensive or Ang II-treated rats. Aortic stiffness, determined by echocardiographic pulse wave velocity, was increased 2.5-fold in Ang II-treated animals but was significantly improved by co-administration of MGE. MGE prevented the Ang II-induced increase in aortic media thickness (Control: 95.8 ± 2.1 μm, Ang II: 135.1 ± 3.7 μm, and Ang II/MGE: 118.2 ± 2.9 μm) and lumen diameter (Control: 2.7 ± 0.2, Ang II: 2.1 ± 0.1 mm, and Ang II/MGE: 2.6 ± 0.1 mm). Nuclear phosphorylated ERK (pERK) in aortic medial cells was increased by 131% in Ang II-treated rats compared to Controls (p < 0.05); MGE co-administration prevented this by 83% (p < 0.001). Ang II-induced aortic fibrosis, measured by total collagen and collagen III, was significantly attenuated in hypertensive animals treated with MGE, in association with reduced pSMAD2 and CTGF. 4-HNE, a marker of lipid peroxidation, and subunits of NADPH oxidases--Nox1, Nox2, p-p47phox--were significantly upregulated by Ang II and normalized with MGE. The inflammatory markers IL-6 and NF-κB were also increased in Ang II-treated aortas (8.9- and 12.7-fold, respectively) and attenuated by MGE. This study is the first to demonstrate that Ang II-induced vascular remodeling is prevented by co-administration of MGE. MGE reduced aortic stiffness, in association with a decrease in fibrotic, oxidative stress, and inflammatory signaling, suggesting that MGE supplementation may improve vascular function in hypertensive patients.