Our previous study found that Chinese yellow wine could inhibit the production of homocysteine (HCY) induced extracellular matrix metalloproteinase-2 (MMP-2) in the cultured rat vascular smooth muscle cells. Little is known about the relationship between Chinese yellow wine and atherosclerosis or MMP-2 in vivo. Thirty-two LDL Receptor knockout mice on a high-fat and L-methionine diet developed plasma hyperhomocysteinemia and atherosclerosis. They were randomly divided into yellow wine group (n = 8), red wine group (n = 8), ethanol group (n = 8), and control group (n = 8), they were sacrificed after 14 weeks. There were no significant differences with plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels in the four groups. Plasma HCY was significantly decreased in the yellow wine group compared to the other three groups (P < 0.01). Yellow wine and red wine groups significantly reduced the atherosclerosis lesion area compared to ethanol and control groups (P < 0.001). However, there was no significant discrepancy between the yellow wine group and red wine group. Compared to the control group and ethanol group, the production of MMP-2 reduced 26.8% and 23.6% in the aortic sinus and the activation of MMP-2 reduced 32.6% and 27.3% in the aortic arch in the yellow wine group; the production of MMP-2 reduced 25.7% and 22.4% in the aortic sinus and the activation of MMP-2 reduced 30.2% and 26.6% in the aortic arch in the red wine group. These results suggest that Chinese yellow wine and red wine can inhibit MMP-2 and improve atherosclerosis, and maybe both Chinese yellow wine and red wine have beneficial effects on cardiovascular disease by inhibiting MMP-2.