Gallic acid (GA), a natural small molecule found in Radix Paeoniae Rubra, has a variety of favorable biological activities. However, the anti-psoriasis effect of GA has never been explored up to now. This study evaluates the protective effect of GA on psoriasis-like skin disease both in vitro and in vivo and explores the underlying mechanism. The results show that GA significantly decreases the mRNA and protein expression of keratin 16 and keratin 17 which are the markers of psoriasis. Additionally, GA obviously ameliorates psoriasis area and severity index scores and decreases the epidermal hyperplasia of psoriasis-like disease mice. The activity of Nrf2 which targets keratin 16 and keratin 17 is significantly downregulated by GA. Furthermore, the downregulation of keratin 16 and keratin 17 induced by GA was abolished by the Nrf2-overexpression in vitro. This study initially elucidates the anti-psoriasis effect and mechanism of GA which hints that GA would be a potential candidate for the treatment of psoriasis.