The inhibitory effects of 25 polyphenols against in vitro allergic reactions were compared using biochemical and cell assays. Three polyphenols including curcumin, gallic acid, and quercetin suppressed the release of β-hexosaminidase from ionophore A23187-stimulated RBL-2H3 cells more effectively (>50% inhibition at 100 μM concentration). They were found to have potencies in suppressing the release of histamine not only from ionophore A23187-, but also from immunoglobulin E (IgE)-stimulated RBL-2H3 cells. Moreover, such suppressive effects of the three polyphenols were also observed in A23187 plus PMA-costimulated rat peritoneal mast cells. The extent of inhibition were quantified as the respective polyphenol concentration that inhibit 50% (IC50) of β-hexosaminidase or histamine release, showing an inhibition tendency with decreasing order of curcumin>gallic acid>quercetin. Down-regulation of Ca2+influx was suggested as the cause of the inhibition of β-hexosaminidase and histamine releases in these cells. The immune process inhibition was confirmed by the observed reduction in the gene expressions and release of proinflammatory cytokine tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-4, due probably to antioxidant activity of the polyphenols. These findings illustrate that curcumin, gallic acid, and quercetin may be beneficial against allergic inflammatory diseases.