The synthesis and utilization of cholesterol are tightly regulated in order to prevent over-accumulation and abnormal deposition within the body. This present study was conducted to characterize the mechanisms which control the cholesterol synthesis as effects of Piper sarmentosum (PS) supplementation in ovariectomy-induced obese rats. Fourty-two female Sprague-Dawley rats were divided into six groups; four treatments (PS, GCA, CTRL and SHM) groups and two basal (B-CTRL and B-SHM) groups. All groups underwent ovariectomy except for the SHM and B-SHM which underwent sham operation. Basal groups were sacrificed on the first day of treatment, while the ovariectomized groups were given PS water extract (0.125g/kg), glycyrrhizic acid (GCA) (0.120g/kg) or water (CTRL) respectively, while the SHM group received only water. After five months of treatment, the rats were killed; blood samples were taken for lipid profile and liver tissue was taken for gene expression analysis. All three ovariectomized groups had a significant increased in the plasma total cholesterol (TC) (p≈0.035), triglyceride (TG) (p≈0.000) and low-density lipoprotein (LDL) (p≈0.005), and significant reduction (p≈0.000) in high-density lipoprotein (HDL) level compared to the SHM group. After 5 months of treatment, both PS and GCA treated group showed a significant reduction in the TC (p≈0.000), TG (p≈0.000) and LDL (p≈0.000) level. Meanwhile for HDL level only PS treated group showed significant (p≈0.013) increment. Both PS and GCA treated group showed a significant up-regulation of the LDL receptor gene but no significant effects on HMGCR, SREBP-2 and APOB gene expression. PS water extract possessed lipid lowering effects as shown by the reduction of TC, TG and LDL and increment of HDL in ovariectomy-induced obese rats. The mechanism for the lipid lowering effect is possibly due to its ability to up-regulate the LDL receptors in ovariectomized-induced obese rats.