Background: Astilbin is a promising candidate drug for psoriasis. However, the poor solubility and stability limited its clinical application. Purpose: The present work aimed to develop a stable microemulsion of astilbin formulation and evaluate its effect in vitro and in vivo. Methods: Oil phase, surfactants, and cosurfactants were screened using solubility and stability of astilbin as the index. The central composite experiment design and response surface methodology analysis were adopted to optimize microemulsion parameters. The particle size, zeta potential, polydispersity index, viscosity, drug content, encapsulation, transmission electron microscopy (TEM), and stability of the optimized microemulsion were evaluated. Then, the drug release and anti-psoriasis effects were evaluated in a mouse model induced by imiquimod. Results: The optimum formulation contained Labrafil M 1944 Cs (10.12%), Polyoxyethylene Castor Oil 35 (37.41%), propylene glycol (12.47%), water (40%), and gallic acid (2.9%), and the average particle size was 14.71 nm. The permeability of astilbin from the optimized astilbin-gallic acid microemulsion in 24 hr was 4.39 times higher compared with the astilbin's microemulsion. The content of astilbin in astilbin-gallic acid microemulsion remained unchanged after being stored at 25 degrees C for 4 months compared with astilbin aqueous (3 h) and astilbin microemulsion (185 h). Compared with the model group, the optimized formulation decreased the PASI score and Baker score by 49% and 73%, respectively, which showed a favorable anti-psoriasis effect. Moreover, there was no difference in the anti-psoriasis effect between the optimized group and the positive control. Conclusion: These results indicated that the astilbin-gallic acid microemulsion might be a potential topical drug used for the treatment of psoriasis.