Although a number of steroidal or non-steroidal anti-inflammatory drugs have been used to treat inflammatory diseases, the discovery of plant-based drugs continues to contribute to new anti-inflammatory agents. In this study, we introduced Dendropanax morbifera Leveille as a potential source for natural anti-inflammatory agents. To investigate the anti-inflammatory activity of D. morbifera leaf extracts and to explore the possible related mechanism, LPS-stimulated RAW 264.7 macrophages were used as a model system. Methanolic extracts from two different stages of D. morbifera leaves (green and senescent leaves) exhibited a strong suppressive effect on the production of LPS-induced pro-inflammatory mediators and cytokines via the suppression of iNOS and COX-2 protein expression and the inhibition of the ERK1/2 signaling pathway. In addition, the quantitative HPLC analysis of phenolic compounds suggested that D. morbifera leaf extracts contained the active phenolic compounds including rutin , chlorogenic acid, (+)−catechin, ferulic acid, myricetin, quercetin, and resveratrol, which have anti-inflammatory effects.