The objective of this study was to investigate the lipid-lowering effects of mulberry water extracts (MWEs). To evaluate the hypolipidemic effect of MWEs, hamsters were fed with either high fat/cholesterol diets (HFCD) or HFCD supplemented with 1 and 2% MWEs for 12 weeks. Plasma total cholesterol (TC) and triglyceride (TG) levels of hamsters fed HFCD with MWEs were significantly reduced by about 30-37% and 16-35%, respectively, as compared to those without MWEs. Similar results were also measured in hepatic TC and TG of hamsters fed HFCD with MWEs. Low-density lipoprotein receptor (LDLR) gene expression and the uptake ability of low-density lipoprotein (LDL) in HepG2 cells were also upregulated by additions of MWEs. MWEs also decreased the gene expressions of enzymes involved in the TG and TC biosyntheses. Results suggest that hypolipidemic effects of MWEs are via an enhancement of LDLR gene expression and the clearance ability of LDL and a decrease in the lipid biosynthesis. Therefore, MWEs could be used as a natural agent against hyperlipidemia.