Atopic dermatitis (AD) is known to aggravate by thymic stromal lymphopoietin (TSLP) and TSLP is also known to up-regulate mast cell proliferation via production of interleukin (IL)-13. Thus, we investigated whether cordycepin could regulate mast cell proliferation induced by TSLP in human mast cell line, HMC-1 cell. Cordycepin significantly diminished the production and mRNA of IL-13 through the down-regulation of phosphorylated-signal transducer and activation of transcription 6 in the TSLP-stimulated HMC-1 cells. Cordycepin also significantly diminished the cell proliferation via down-regulating MDM2 and Bc12 levels and up-regulating p53, caspase-3, and cleaved poly ADP-ribose polymerase levels in the TSLP-stimulated HMC-1 cells. Moreover, cordycepin significantly diminished the production of IL-6, tumor necrosis factor-alpha, and IL-1 beta in the TSLP-stimulated HMC-1 cells. In conclusion, our study shows that cordycepin has potential effect for the treatment of allergic inflammatory diseases through the blockade of IL-13 and MDM2 exacerbated by TSLP.