In the present study, 17 coumarins were evaluated for cholesterol-lowering activity in rats fed a high-fat diet. Two statins, atorvastatin and simvastatin, were used as positive controls. Each group consisted of eight rats; weight gain, food intake, and feed efficiency ratio within 4 weeks were determined. Four biochemical parameters (total cholesterol, low-density lipoprotein, high-density lipoprotein, and total glycerides) were determined in each tested group. Atherogenic index, cardiac risk factor, and liver indexes were also calculated to explain structure-activity relationships of coumarins. With the results of weight gain and food intake, the feed efficiency ratio (FER) was calculated for the 17 coumarins. The positive control groups did not recover FER values to the level of the normal group. The high-fat diet increased concentrations of total cholesterol, low-density lipoprotein, and total glycerides in the control rats as compared to the normal rats, whereas high-density lipoprotein decreased in the control rats. The two statins and all coumarins lowered cholesterol and increased high-density lipoprotein level to those of the normal rats. 7-Methoxycoumarin was the highest cholesterol-lowering coumarin and showed potent recovery rate of cardiac risk factor, and the atherogenic and liver indices as compared to the normal rats. Structure-activity analyses of coumarins implicated a double bond at C3-C4 and a methoxy group at C7 as being essential for the cholesterol-lowering activity. 7-Methoxycoumarin may partially inhibit the intestinal absorption of cholesterol by interfering with micelle formation.