The goal of this study was to investigate the topical anti-inflammatory effects of the megamolecular polysaccharide sacran extracted from cyanobacterium Aphanothece sacrum using various inflammatory animal models. Sacran showed potent anti-inflammatory effects with optimum effective concentrations at 0.01 and 0.05% (w/v). Sacran markedly inhibited paw swelling and neutrophil infiltration in carrageenan-induced rat paw edema. Additionally, 6,7-dimethoxy-1-methyl-2(1H)-quinoxalinone-3-propionyl-carboxylic acid (DMEQ)-labeled sacran had the ability to penetrate carrageenan-induced rat paw skin rather than normal skin. Also, sacran significantly suppressed kaolin-induced and dextran-induced rat paw edema throughout the duration of the study. Furthermore, sacran significantly suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema and mRNA expression levels of cyclooxygenase (COX)-2 as well as pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Safety of sacran solution was verified by negligible cytotoxicity in HaCaT cells. These results suggest that sacran may be useful as a therapeutic agent against inflammatory skin diseases with no life-threatening adverse effects.