Dihydromyricetin (DMY), a flavonoid, belongs to a class of natural compounds and possesses anti-inflammatory properties. The objective of this research is to investigate the effects and mechanism of DMY in mice induced by imiquimod (IMQ). Here, DMY ointment was topically applied to evaluate the effect of DMY on psoriasis, while the results showed DMY improved clinical phenotype of IMQ-induced psoriasiform dermatitis. Histological evaluation revealed decreases in keratinocyte hyperplasia and immune cell infiltration in mice after DMY administration. Besides, DMY treatment could attenuate psoriasiform inflammation as showed in the decreased expression of inflammation mediators such as IL-17a, IL-23a, TNF-α, IL-6, IL-1β, IL-12a, CXCL2, and S100A8 in the skin of mice. Mechanistically, DMY reduced the polarization of macrophages towards the pro-inflammatory M1 phenotype by inhibiting the TLR4/NF-κB pathway, importantly, which subsequently regulated the differentiation of T helper (Th) 1 and Th17 cell subsets, leading to the relief of immune inflammatory response in psoriasis. In conclusion, the research reveals that DMY markedly attenuated IMQ-induced psoriasis in mice and provides that DMY have great potential for treatment of psoriasis.