Psoriasis is a chronic, inflammatory skin disease with high incidence and high rates of relapse, for which no satisfactory treatments are currently available. Yes-associated protein (YAP) is highly expressed in psoriasis and may regulate the proliferation and apoptosis of keratinocytes. Danshen is a traditional Chinese medicine, commonly used in the treatment of psoriasis. Danshensu is the most abundant water-soluble component of Danshen, but its therapeutic mechanism is still unclear. In this study, MTT was used to detect the effects of different danshensu concentrations (0.125, 0.25, 0.5 mmol/l) on the proliferation of an M5-based psoriasis cell model. The effects of danshensu on cell cycle and apoptosis were detected by flow cytometry. Cyclins and apoptosis-related proteins were evaluated by Western blot. Danshensu (20, 40, 80 mg/kg/day) was administered intraperitoneally to the imiquimod (IMQ) psoriasis mouse model. After 7 days, the expression of YAP in the lesions was detected by immunohistochemistry and Western blot. We found that danshensu reduced the expression of YAP in the M5 psoriasis cell model, inhibited cell proliferation, induced cell cycle arrest in G0/G1 phase, and promoted cell apoptosis. All these effects were partly reverted by YAP overexpression. The skin lesions of IMQ mice were thinned and the scales reduced after intragastric administration of danshensu, which also resulted in dose-dependent inhibition of YAP expression. We concluded that danshensu prevents abnormal epidermis proliferation in psoriasis possibly by modulating YAP expression. Our work can provide a theoretical basis for the clinical application of Danshen in the treatment of psoriasis.