Licochalcone A is a chalcone isolated from the roots of Glycyrrhiza inflate. In this study, we examined the effects of licochalonce A on the production of cytokines in LPS-activated macrophages. Licochalcone A inhibited the secretion of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α. The reduced secretion of proinflammatory cytokines is related to the differences in the mRNA expression of IL-1β, IL-6, and TNF-α. Moreover, licochalcone A inhibited the mRNA expression of IL-12p40, IL-18, and IL-23p19. To investigate its mechanism, we performed gel shift assay. Licochalcone A reduced nuclear NF-κB binding activity in LPS-activated RAW264.7 cells. Taken together, these results suggest that licochalcone A has anti-inflammatory effects in LPS-activated macrophages and its mechanism could be through the down-regulation of binding to the κB site.