In the present study, we report that topical application of silymarin reduces chemical-induced irritant contact dermatitis in mice. Topical application of 2,4-dinitrochlorobenzene (DNCB) induced an ear swelling in BALB/c mice and silymarin suppressed DNCB-induced increase in ear thickness. Prophylactic and therapeutic application of silymarin showed similar effect on DNCB-induced increase in ear thickness and skin water content. In addition, phobor ester- or croton oil-induced increase in ear thickness was also inhibited by silymarin treatment. Silymarin also blocked neutrophil accumulation into the ear induced by these irritants. Further study demonstrated that DNCB-induced expression of tumor necrosis factor-α (TNF-α), KC and adhesion molecules in mouse ear was suppressed by silymarin. Moreover, TNF-α-induced expression of cytokines, such as TNF-α and IL-1β, and a chemokine, IL-8, were suppressed by silymarin treatment in human keratinocyte cell line, HaCaT. Silymarin also blocked TNF-α- and DNCB-induced NF-κB activation in HaCaT. Collectively, these results demonstrate that topically applied silymarin inhibits chemical-induced ICD in mice and this might be mediated, at least in part, by blocking NF-κB activation and consequently inhibiting the expression of cytokines and adhesion molecules.