Psoriasis is a type of chronic autoimmune-mediated inflammatory skin condition in which clinical manifestations are characterized by erythema and scaly changes, with complex pathogenesis and ease of relapse, and it is difficult to cure. Lenalidomide (Len) is a structural analog of thalidomide, which belongs to the second generation of immunomodulators and has the functions of tumor killing, immune regulation, anti-angiogenesis and regulation of the myeloma microenvironment. In the current experiment, we investigated the therapeutic effect of transdermal application of Len on the pathological changes of imiquimod (IMQ)-induced skin irritations and inflammation in psoriatic-like mice. The in vivo results revealed that Len nanoemulsion-based gels markedly reduced the IMQ-induced Psoriasis Area Severity Index (PASI) score, spleen-to-body weight index and CD4 protein expression in the derma of mice and improved IMQ-induced skin inflammatory cell infiltration. Transcriptome sequencing was intended to obtain the differentially expressed genes among the skin of Con mice and the skin of IMQ mice, and then, the GO enrichment classification and KEGG pathway analysis of the significant genes was executed to obtain major signaling pathways in the pathogenesis of the psoriasis mouse model. It was found that the PI3K/AKT signaling pathway was a major pathway in the pathogenesis of psoriasis in a mouse model induced by IMQ. The immunohistochemical results confirmed that Len could modulate the protein expression of AKT and NF-κB in skin. In conclusion, the protective effect of transdermal administration of Len may be related to the inhibition of the PI3K/AKT signaling pathway and its downstream NF-κB pathway against IMQ-induced psoriasis in mice.