Psoriasis is a most common chronic autoimmune-arbitrated cutaneous inflammatory skin disorder by unclear pathogenesis. In this current study we demonstrated the effect of galangin (GAL) on imiquimod (IMQ)-induced psoriasis-like skin inflammation and decipher its possible protective mechanism which has not been investigated. The in vivo results revealed that GAL at 1% w/w and 2% w/w for six consecutive days markedly reduced IMQ-induced PASI scoring, skin, ear thickness, hematological markers, levels of nitrites, TBARS, MPO, histopathological, as well modulated the protein levels of pro-inflammatory mediators of COX-2, iNOS, NF-κB pathway and pro-inflammatory cytokines IL-17, IL-23, IL-1β in the skin and also IL-6, TNF-α in both skin and serum. Besides, GAL restored the levels of antioxidants markers such as SOD, CAT, GST, GSH, GR and Vit-C, anti-inflammatory cytokine of IL-10, and the protein levels of Nrf2/HO-1 in the skin compared to the IMQ group. Finally, our study demonstrates that GAL exerted its protective effect by up-regulating the anti-inflammatory and the antioxidant markers against psoriasis pre-clinical models indicating its potency for treating psoriasis in humans.