Chrysin is a natural, biologically active compound extracted from many plants, honey and propolis. It possesses potent anti-inflammation, anti-cancer and anti-oxidation properties. The mechanism by which chrysin suppresses COX-2 expression remains poorly understood. In the present report, we investigated the effect of chrysin on the expression of COX-2 in lipopolysaccharide (LPS)-activated Raw 264.7 cells. Chrysin significantly suppressed the LPS-induced COX-2 protein and mRNA expression in a dose-dependent manner. The ability of chrysin to suppress the expression of the COX-2 was investigated using luciferase reporters controlled by various cis-elements in COX-2 promoter region. Mutational analysis and electrophoretic mobility shift assay verified that nuclear factor for IL-6 was identified as responsible for the chrysin-mediated COX-2 downregulation. These results will provide new insights into the anti-inflammatory and anti-carcinogenic properties of chrysin.