Allergic diseases are chronic inflammatory conditions with specific immune and inflammatory mechanisms. Scientific interest in understanding the mechanisms and discovering novel agents for the prevention and treatment of allergic disease is increasing. Streptochlorin, a small compound derived from marine actinomycete possesses anti-angiogenic and anti-tumor activities. However, the anti-allergic effects and underlying mechanisms remain to be elucidated. In the present study, we investigated the effect of streptochlorin on allergic responses in vitro and in vivo. Streptochlorin inhibited degranulation and production of tumor necrosis factor-α and IL-4 by antigen-stimulated mast cells. Streptochlorin also inhibited the phosphorylation of Akt and the mitogen-activated protein kinases (MAPKs), including p38, ERK, and JNK. Further, streptochlorin reduced the phosphorylation of Syk in RBL-2H3 cells and inhibited the activity of Lyn and Fyn. Furthermore, administration of streptochlorin suppressed the allergic reactions in both passive cutaneous anaphylaxis reaction and 2, 4-dinitrofluorobenzene (DNFB)-induced allergic dermatitis in mice model. Considering the data obtained, we report for the first time that streptochlorin possess anti-allergic properties. The underlying mechanism of streptochlorin in exhibiting potent anti-allergic activity might be through the inhibition of the Lyn/Fyn and Syk signaling pathways.