This study was conducted to investigate the anti-inflammatory activity of Desmarestia ligulate (D. ligulate) leaf. The effects on cell viability and anti-inflammatory activities of D. ligulata leaf extract, as well as those of D-mannuronic acid (DMA), on RAW 264.7 cells (macrophages) and peripheral blood mononuclear cells (PBMCs) during inflammation-induced stress were analyzed by determining the levels of NO, IL-17, IL-4, and TNF-α using ELISA and evaluating the expression of iNOS and MPO genes. D. ligulata leaf extract and DMA exhibited low toxicity in RAW 264.7 cells and PBMCs, which secreted lower levels of TNF-α and IL-4. The anti-inflammatory effect of DMA was higher than that of D. ligulata leaf extract as indicated by the levels of the inflammatory cytokine IL-17. Furthermore, treatment with D. ligulata leaf extract and DMA decreased the expression of iNOS and MPO genes after stress induction. These findings suggested that D. ligulata leaf extract and DMA exert anti-inflammatory effects as well as regulate cytokine release activities and inflammatory gene expression. Therefore, D. ligulata leaf extract and DMA may be used as cosmetic materials to control skin inflammation.