The activation of microglia induces the overproduction of inflammatory mediators that are responsible for the neurodegenerative disorders including Alzheimer`s disease and Parkinson`s disease. The large amounts of prostaglandin E2 (PGE2) produced by inducible cyclooxygenase (COX-2) is one of the main inflammatory mediators that can contribute to neurodegeneration. The inhibition of COX-2 thus may provide therapeutic strategy for the treatment of neurodegenerative diseases. From the activity guided purification of EtOAc soluble fraction of Siegesbeckia glabrescens, four compounds were isolated as inhibitors of PGE2 production in LPS-activated microglia. Their structures were determined as 3, 4`-dimethylquercetin (1), 3, 7-dimethylquercetin (2), 3-methylquercetin (3) and 3, 7, 4`-trimethylquercetin (4) by the mass and NMR spectral data analysis. The compounds 1-4 showed dose-dependent inhibition of PGE2 production in LPS-activated microglia with their IC50 values of 7.1, 4.9, 4.4, 12.4 uM respectively. They reduced the expression of protein and mRNA of COX-2 through the inhibition of I-kBa degradation and NF-kB activity that were correlated with the inactivation of p38 and ERK. Therefore the active compounds from Siegesbeckia glabrescens may have therapeutic effects on neuro-inflammatory diseases through the inhibition of overproduction of PGE2 and suppression of COX-2 overexpression.