A novel thermostable form of piperlonguminine (GB-N) was extracted from medicinal plant Piper longum in efforts to explore the bioactive components underlying the mechanism of Piper longum in reducing plasma lipids. In vitro, HepG2 cells were employed to investigate the effects of GB-N on regulating cellular total cholesterol and low-density lipoprotein (LDL) receptor (LDLR) mRNA abundance, while high-fat and high-cholesterol diet-induced hyperlipidemic Wistar rats were used to investigate in vivo effects of GB-N. Cellular total cholesterol assay showed that GB-N dose-dependently reduced cellular total cholesterol in HepG2 cells in the presence and absence of elevated plasma cholesterol levels by 25% and 32%, respectively. Reverse transcription PCR assay showed that LDLR mRNA abundance was up-regulated dose-dependently by 142% via GB-N treatment in HepG2 cells. Animal experiment revealed that GB-N dose-dependently reduced serum total cholesterol by 26%, triglyceride by 47%, LDL cholesterol by 30%, while increased serum high-density lipoprotein (HDL) cholesterol by 524% in diet-induced hyperlipidemic Wistar rats. In conclusion, the results suggest the potential therapeutic uses of GB-N in the prevention and treatment of hyperlipidemia and related diseases.