Immune-mediated inflammation contributes to the development of psoriasis. However, long-term treatment with global immunosuppressive agents may cause a variety of side effects including recurrent infections. Kaempferol (KP), a natural flavonol, present in various plants is proposed to be useful for the treatment of psoriasis patients. Nevertheless, an explicit understanding of KP induced mechanisms is a prerequisite for its use in clinics. Therefore, we investigated the therapeutic effects and potential mode of action of KP using IFN-γ induced HaCaT cells and imiquimod-induced psoriasis-like skin lesions in mice. In this study, we found KP reduced intracellular ROS production, inhibited rhIFN-γ-induced IFN-γR1 expression, and up-regulated SOCS1 levels in HaCaT cells. In addition, KP inhibited rhIFN-γ-induced phosphorylation of JAK-STAT signaling molecules in HaCaT cells. Most importantly, KP alleviated imiquimod-induced psoriasis-like skin lesions in mice, histopathology and proportion of DCs in the skin. Besides, it reduced the population of γδT17 cells in the lymph nodes of the psoriatic mice and also decreased the gene expression of many proinflammatory cytokines, including interleukin IL-23, IL-17A, TNF-α, IL-6, and IL-1β in addition to down-regulation of the proinflammatory JAK-STAT signaling pathway. Thus, KP modulated IFN-γ induced JAK-STAT signaling pathway by inducing IFN-γR1 expression and up-regulating SOCS1 expression. In addition, KP also ameliorated imiquimod-induced psoriasis by reducing the dendritic cell numbers, and γδT17 cell population, along with down- modulation of the JAK-STAT pathway. © 2022 Elsevier B.V.