N-acetylgalactosaminyltransferase 2-Angiopoietin-like protein 3-lipoprotein lipase (GALNT2-ANGPTL3-LPL) pathway may be a useful pharmacologic objective for dyslipidemia. The present study was conducted to test the effect of paeoniflorin, a monoterpene Glycoside, on dyslipidemia in mice. Fifty mice were randomly divided into five groups (n = 10): three groups of apolipoprotein E-null (ApoE-/-) mice treated with paeoniflorin (10 or 20 or 30 mg/kg/day), untreated ApoE-/- mice group, and C57BL/6J control group. Six weeks after treatment, expression of hepatic ANGPTL3, hepatic GALNT2 and adipose tissue LPL, lipid levels in the liver and blood were quantified. Treatment with paeoniflorin (10 or 20 or 30 mg/kg) obviously down-regulated expression of ANGPTL3 and up-regulated expressions of GALNT2 and LPL concomitantly with elevated plasma high-density lipoprotein cholesterol level, reduced plasma concentrations of low-density lipoprotein cholesterol, total cholesterol, triglyceride, malonaldehyde, and 8-isoprostane. The present results suggest that paeoniflorin regulates GALNT2-ANGPTL3-LPL pathway to attenuate dyslipidemia in mice.