This study aimed to investigate the therapeutic effect and possible mechanism of carboxyamidotriazole (CAI) on imiquimod (IMQ)-induced psoriasis-like mice model and M5 (IL-1α, IL-17A, IL-22, TNF-α and oncostatin M)-induced keratinocytes model of psoriasis. The severity of psoriasis-like skin lesion in mice was evaluated by psoriasis area and severity index (PASI) score. The histopathological changes of skin were examined by hematoxylin-eosin staining and Baker score was calculated. The levels of pro-inflammatory cytokines in skin were measured by enzyme-linked immunosorbent assay. Transcriptome sequencing technique was used to analyze differentially expressed genes (DEGs) and real-time quantitative PCR (qPCR) was used to detect mRNA expressions. The animal experiments conducted in this study were approved by the Institutional Animal Care Use & Welfare Committee of Institute of Basic Medical Sciences, Chinese Academy of Medical Science (grant No. ACUC-A02-2022-115). The results showed that CAI significantly improved the severity of psoriasis-like lesion, reduced PASI score, attenuated pathological changes, decreased Baker score and inhibited the levels of IL-1β, IL-6, IL-17A, IL-23 and TNF-α in skin of IMQ-induced mice. Transcriptome sequencing analysis revealed that regulating keratinocytes and their mediated keratinization might be involved in the mechanism of CAI. Further qPCR study validated that CAI down-regulated the mRNA expression of DEG S100a7. Moreover, the keratinocyte model of psoriasis was established by stimulating HaCaT cells by M5. It was shown that CAI decreased the mRNA expression levels of S100a7, Il1β, Il6, Il17, Il23 and Ccl20, which were up-regulated by M5 stimulation. In conclusion, CAI might have a good therapeutic efficacy on psoriasis, and its mechanism was related to regulate the function of keratinocytes and downregulate cytokines and S100a7.