In this study, the anti-inflammatory effects of Monostroma crassidermum Tokida ethanol extract (MCEE) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and croton oil-stimulated ICR mouse models were investigated. MCEE reduced the secretion of pro-inflammatory cytokines, including interleukin-6, IL-1β, tumor necrosis factor-α, and nitric oxide, which are non-toxic to RAW 264.7 cells. In vivo testing showed that the results in the MCEE-treated group (10-250 mg/kg. body weight) were similar to those in the prednisolone-treated group (10 mg/kg. body weight). Photomicrographs showed that the skin layer was thinned, and mast cell infiltration was reduced in the mouse-ear tissue. Therefore, these results suggested that MCEE exerts an anti-inflammatory effect, indicating the possible applications of MCEE as a natural anti-inflammatory material.