The inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) is considered able to decrease serum cholesterol levels and dramatically reduce the risk for cardiovascular and cerebrovascular diseases. The statins, competitive inhibitors of HMGCR, have been employed to control hypercholesterolemia. But their side effects, especially their safety of long-term administration have attracted great attention. Therefore, there is still an urgent requirement for the development of safer inhibitors of HMGCR with less serious side effects. In this study, we cloned and purified the catalytic domain of human HMGCR (△HMGCR), and applied the method of Ultra Performance Liquid Chromatography (UPLC) to assay △HMGCR activity and screen its inhibitors from natural products. The results indicated that EGCG can inhibit △HMGCR in the presence of some glycerol in vitro and can decrease cellular total cholesterol in HepG2 cells. As a consequence, it is promising to put EGCG into the development of hypolipidemic health product.