Mast cells play a critical role in allergic diseases. Therefore, development of new therapeutic agents that suppresses the activation of mast cells may help prevent or treat allergic diseases. Here, we investigated the anti-allergic effects of 4-chloro-cinnamaldehyde and 4-trifluoro-cinnamaldehyde in RBL-2H3 cells. β-Hexosaminidase assays revealed that degranulation of RBL-2H3 cells was decreased following treatment with 60 μM 4-chloro-cinnamaldehyde or 4-trifluoro-cinnamaldehyde. Moreover, quantitative real-time reverse transcription polymerase chain reaction showed that the relative expression levels of tumor necrosis factor-α, interleukin-4, and cyclooxygenase-2 mRNAs were decreased in RBL-2H3 cells treated with 4-chloro-cinnamaldehyde and 4-trifluoro-cinnamaldehyde in a concentration-dependent manner. Additionally, 4-chloro-cinnamaldehyde blocked the phosphorylation of MKKs and MAPKs. These data clearly suggested that 4-chloro-cinnamaldehyde and 4-trifluoro-cinnamaldehyde had inhibitory effects on the inflammatory responses of mast cells and may have potential as novel therapeutic agents for the prevention or treatment of allergic diseases.