The lipid-lowering efficacy of hesperetin was revealed in preliminary studies on experimental animals. As such, the current study compared the effect of hesperetin 7-O-lauryl ether, with that of hesperetin and lovastatin on the lipid profile and cholesterol-regulating mechanism in high-cholesterol-fed rats. Male rats were fed a high-cholesterol diet (1%, wt/wt) or high-cholesterol diet supplemented with lovastatin (1, 0.02%, wt/wt), hesperetin (2, 0.02%, wt/wt), or hesperetin 7-O-lauryl ether (3, 0.031%, wt/wt) for six weeks. The supplemental amount of 3 was 0.066mmol/100g diet as an equivalent to the supplemental amount of 2. The plasma total cholesterol and triglyceride levels were significantly lowered by the 2 and 3 supplements compared with the control or 1-supplemented group. The hepatic HMG-CoA reductase activities were also significantly lower in all the supplemented groups compared with the control group, and the hepatic ACAT activity was significantly lower in the 2- and 3-supplemented groups. The supplementation of 3 resulted in a higher excretion of total neutral sterol and total fecal sterol compared with the control or 1-supplemented group. Accordingly, overall, compound 3, exhibited a more potent plasma lipid-lowering effect than compound 1 based on inhibiting cholesterol biosynthesis and esterification, while also increasing the fecal sterol excretion.