Psoriasis is a common inflammatory disease. It affects 1-3% of the population worldwide and is associated with increasing medical costs every year. Typical psoriatic skin lesions are reddish, thick, scaly plaques that can occur on multiple skin sites all over the body. Topical application of imiquimod (IMQ), a toll-like receptor (TLR)7 agonist and potent immune system activator, can induce and exacerbate psoriasis. Previous studies have demonstrated that isoflavone extract has an antioxidant effect which may help decrease inflammation and inflammatory pain. Through in vivo studies in mice, we found that the topical application to the shaved back and right ear of mice of isoflavone extract prior to IMQ treatment significantly decreased trans-epidermal water loss (TEWL), erythema, blood flow speed, and ear thickness, while it increased surface skin hydration, and attenuated epidermal hyperplasia and inflammatory cell infiltration. Through in vitro experiments, we found that isoflavone extract can reduce IL-22, IL-17A, and TNF-α-induced MAPK, NF-κB, and JAK-STAT activation in normal human epidermal keratinocytes. At the mRNA level, we determined that isoflavone extract attenuated the increased response of the TNF-α-, IL-17A-, and IL-22- related pathways. These results indicate that isoflavone extract has great potential as an anti-psoriatic agent and in the treatment of other inflammatory skin diseases.