Andrographolide (AND) and neoandrographolide (NEO) are the diterpenoids from the Andrographis paniculata (Acanthaceae). It is reported the diterpenoids exhibit a wide spectrum of biological activities. The aim of this study was to investigate the hypolipidemic effect of AND and NEO in hyperlipidemic mice induced by 75% yolk emulsion and in hyperlipidemic rats induced by high fat emulsion, respectively. The results showed that the levels of triglyceride, total cholesterol (TC) and low-density lipoprotein cholesterol were reduced by AND and NEO in a dose-dependent tendency in mice. Compared with the model group, the plasma TC levels of experimental groups with AND and NEO at 100 mg/kg dosage decreased by 23.9 and 20.2% in rats, respectively (P < 0.05). It was also found that the plasma aspartate transaminase and alanine transaminase levels were significantly decreased by feeding with AND and NEO in rats, compared with positive group (simvastatin) (P < 0.01). Otherwise, AND and NEO could protect the cardiovascular due to down-regulation of iNOS expression and up-regulation of eNOS expression. In conclusion, AND and NEO have potent hypolipidemic effects and protect the cardiovascular without significant liver damage. Copyright © 2012 John Wiley & Sons, Ltd.