Background: Glabridin is one of the main components of the isoflavonoids in Glycyrrhiza glabra and possesses anti-inflammatory, anti-bacterial, and anti-cancer effects. Objectives: Herein, the therapeutic effects and mechanisms of action of the glabridin liposome (GL) complex were studied in mice with imiquimod-induced psoriasis. Materials and Methods: After treatment with GLs, their effectiveness was assessed using parameters, such as Psoriasis Area and Severity Index (PASI) score, histopathology, inflammatory cytokines, and psoriasis-associated proteins. Results: The results demonstrated that GLs could significantly improve psoriatic symptoms, downregulate mast cell infiltration, and significantly reduce the PASI score of psoriatic mice. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) results showed that GLs significantly decreased IL-23 and STAT3 mRNA expression. The results of immunohistochemistry and the enzyme-linked immunosorbent assay indicated that GLs decreased the expression of tumor necrosis factor-alpha (TNF-α), IL-17, and IL-22. Conclusion: GLs can alleviate psoriasis by inhibiting the expression of keratinocyte-activating proteins. These results suggest that GLs have great potential for the clinical treatment of psoriasis. [ABSTRACT FROM AUTHOR]