To reduce cardiovascular disease (CVD) by reducing circulating cholesterol concentrations, much attention has been focused on the search for dietary interventions for hypercholesterolemia. Corni Fructus is known to exhibit several biological activities. Therefore, in the present study, its protective effect on diet-induced hypercholesterolemia was studied using a rat model fed 1% cholesterol and 0.5% cholic acid. Corni Fructus extract was administered at an oral dose of 50, 100, or 200 mg/kg of body weight/day for 10 days. The administration inhibited the elevation of both systolic and diastolic blood pressure. In addition, it lowered serum total cholesterol levels with a decrease in esterified cholesterol. Moreover, the atherogenic index was decreased in a dose-dependent manner, suggesting its protective role against CVD through regulating cholesterol and lipoprotein levels. The hepatic levels of total and free cholesterol were also reduced by Corni Fructus. This implies that free cholesterol was used for catabolism or efflux. Consequently, the levels of total cholesterol and bile acid in feces were significantly increased. Our present results also showed that the administration of Corni Fructus decreased lipid peroxidation, suggesting a protective effect against oxidative stress induced by hypercholesterolemia. Furthermore, hypercholesterolemic control rats had significantly lower expression of sterol regulatory element-binding protein (SREBP)-2 protein without any difference in SREBP-1 protein expression. On the other hand, the protein expression of SREBP-2 was significantly up-regulated by Corni Fructus. Furthermore, the protein expression of peroxisome proliferator-activated receptor alpha was elevated, indicating that Corni Fructus would activate fatty acid oxidation. In conclusion, Corni Fructus may protect against CVD by regulating blood pressure, cholesterol levels, and expression of proteins related to lipid metabolism.