Psoriasis is a chronic recurrent skin inflammatory disease, and inhibition of inflammation may be an effective means of treating psoriasis. The flavonoid genistein has a clear anti-inflammatory effect. However, the anti-psoriatic effects of genistein and their underlying mechanisms remain unclear. In this study, we investigated the effects of genistein on imiquimod (IMQ)-induced psoriasis-like skin lesions in vivo and explored the mechanisms underlying those effects in vitro. It was found that genistein can significantly improve IMQ-induced pathological scores of cutaneous skin lesions in mice, reduce epidermal thickness, and inhibit the expression of inflammatory factors, including interleukin (IL)-1 beta, IL-6, tumour necrosis factor-alpha (TNF-alpha), chemokine ligand 2 (CCL2), IL-17 and IL-23. In vitro studies, genistein inhibited the proliferation of human keratinocyte HaCaT cells and inhibited the expression of inflammatory factors in a dose-dependent manner which induced by TNF alpha. Further researches showed that genistein could also significantly inhibit phosphorylated STAT3 (pSAT3) expression in IMQ mice dorsal skin and in TNF-alpha-induced HaCaT cells. The inhibitory effect of genistein on the expression of IL-6, IL-23 and TNF-alpha was weakened after Stat3 siRNA in HaCaT cells. Genistein could also significantly inhibit TNF-alpha induced the nuclear translocation of NF-kappa B, and inhibit the phosphorylation of I-kB alpha (pI-kB alpha). After combining with NF-kappa B blocker BAY 11-7082, the effect of genistein down-regulate the expression of TNF-alpha and VEGFA was attenuated in HaCaT cells. The results suggest that genistein may be developed for the treatment of psoriasis lesions.