High-fat diets (HFDs) supplemented with the L-Trp and L-Leu-OEt derivatives of the monascus pigment were fed to mice. Compared to the HFD group, the average body weight gain of the four HFD-pigment groups was decreased by 13.6-50.9%, and the intra-peritoneal adipose tissues weight was reduced by 16.7-30.5%. The derivatives also reduced the respective serum total cholesterol and triglyceride levels of the mice by 9.7-14.4% and 12.5-17.2%. The L-Trp derivative greatly increased the HDL-cholesterol level by 64.8-66.4% and the HTR value by 73.8-81.7%. The L-Leu-OEt and L-Trp derivatives decreased the total cholesterol level in the mice liver by 9.7-24.2% and 36.2-39.9%, respectively. Reductions in the triglyceride level were 21.5-22.4% for the L-Leu-OEt derivative and 17.9-18.8% for the L-Trp derivative. The L-Leu-OEt derivative exhibited higher in vitro inhibitory activities against HMG-CoA reductase and lipoprotein lipase than the L-Trp derivative. An in vivo test with mice showed the L-Trp derivative to have higher anti-obesity effects than the L-Leu-OEt derivative.