Castanea extracts are known to have antioxidant properties and are used as a traditional medicine in China and Asia. However, the biological activity of Castanea seguinii Dode has remained to be fully elucidated. The present study investigated the anti-inflammatory effects of a Castanea seguinii Dode methanolic extract (CSME) on lipopolysaccharide-induced RAW264.7 macrophage cells. CSME inhibited the production of nitric oxide (NO) and the expression of inducible NO synthase. It also suppressed the production of the pro-inflammatory cytokines inteleukin-6 and tumor necrosis factor-α, as well as chemokine monocyte chemoattractant protein 1. In addition, CSME inhibited nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, while also downregulating transcription factor activator protein-1. Furthermore, CSME increased heme oxygenase 1 through the upregulation of NF (erythroid-derived 2)-like-2 (Nrf-2), which directly or indirectly affects inflammation. It also increased the phosphorylation of 5'-adenosine monophosphate-activated protein kinase (AMPK). In conclusion, CSME was demonstrated to exert its anti-inflammatory activities through the inhibition of the NF-κB and the MAPK signaling pathways, as well as the activation of Nrf-2 and AMPK. These results indicated that CSME may be a promising for development as a commercial anti-inflammatory medicine.