Mast cells are key effector cells in the early phase allergic inflammation and in diverse immunological and pathological processes. In order to understand the effect on reduction of the anti-dinitrophenyl (DNP) IgE antibody-induced β-hexosaminidase release in RBL-2H3 rat mast cells, a novel series of 4-senecioyloxymethyl- 6,7-dimethoxycoumarins (SMDC) was prepared by reacting 4-chloromethyl-6,7-dimethoxycoumarin with various carboxylic acids. Compounds 8-11 with cyclic moiety such as phenyl, thiophenyl, pyridinyl, and furanyl group were found to inhibit-hexosaminidase release more potently (5.98-9.62 μM) than compounds 3- 7 and 12 with acyclic moiety (19.32-76.78 μM). Furthermore, compounds 8 and 9 inhibited IgE-induced ear swelling and significantly reduced systemic passive cutaneous anaphylaxis reaction in mice.