Abstract Psoriasis is an autoinflammatory skin disease characterized by the abnormal activation of epidermal keratinocytes. The Hippo-YAP pathway is an evolutionarily conserved pathway that plays important roles in organ size control and tumorigenesis. Recently, accumulating evidence demonstrated that YAP1, the core downstream component of Hippo-YAP pathway, was up-regulated in psoriasis patients, suggesting its possible role in psoriasis development. However, its precise function and mechanism in psoriasis pathogenesis are still not well-clarified. In the present study, we confirmed the up-regulation of YAP1 in psoriasis keratinocytes by measuring its expression in psoriatic patient skins, psoriatic-like cellular model, and IMQ-induced mouse model. Further functional studies showed that YAP1 promoted keratinocyte proliferation and inflammation in vitro. Meanwhile, VP, a selective YAP1 antagonist, inhibited keratinocyte proliferation and inflammatory factor production in a dose-dependent way. Moreover, intradermal injection of si-Yap1 or VP hindered psoriasis development by impeding epidermal hyperplasia and relieving systemic inflammatory response in the IMQ-induced mouse model. Therefore, our findings suggest that YAP1 plays a crucial role in psoriasis pathogenesis through modulating keratinocyte activation and may serve as a novel target for the treatment of psoriasis.