Flavonoids are natural active components. They distribute widely in edible plants with high activity of anti-inflammation. Inhibition of cyclooxygenase-2(COX-2) was determined by real-time fluorescent quantitative olymerase chain reaction (RTFQ-PCR). And structure characteristics of flavonoids for COX-2 inhibition were mainly analyzed by a quantitative structure activity relationship (QSAR) model. Descriptors such as SMR_VSA5, vsurf_DD12, reactive were the top three important independent variables to COX-2 mRNA inhibiton in RAW264.7. Low SMR_VSA5 value meant a lower molecular refractivity resulting in a lower COX-2 mRNA inhibition. High vsurf_DD12 value related to poor molecular balance and showed profound adverse to COX-2 mRNA inhibition. Reactive group in this paper referred to C2-C3 double bond contributed negatively to COX-2 mRNA inhibition. Glycosidic and C3-OH substitutions may lower SMR_VSA5 value. It indicated that flavanones such as hesperetin, naringenin, liquiritigenin were efficient to repress COX-2 mRNA and they were potential anti-inflammatory natural products. Further, substitution with a glucopyranosyl at C-6 resulted in a poorer molecule balance than that at C-8 and a lower COX-2 mRNA inhibiton accordingly. This may expain why orientin and vitexin exhibited better anti-inflammatory activity than their isomers homoorientin and isovitexin. Also, methoxyl groups at C-4' may also be a favorable flavonoid structural characteristic for COX-2 mRNA inhibiton. These results provide valuable information on understanding the high anti-inflammatory activity of flavonoids.