Background: Psoriasis is a chronic, immune-mediated, inflammatory skin disease characterized by abnormal keratinocyte proliferation, in which M1 macrophage polarization plays a critical role. However, the specific biomarkers and mechanisms underlying macrophage polarization in psoriasis remain unclear. Methods: We analyzed the psoriasis dataset (GSE14905) to identify differentially expressed genes and applied weighted gene co-expression network analysis to identify key module genes. Macrophage polarization-related (MPR) genes were extracted from the Rummagene database, and MPR genes in psoriasis were identified through Venn analysis. Functional enrichment analysis (GO/KEGG) revealed associated pathways, while six CytoHubba algorithms determined hub genes, with diagnostic potential assessed via ROC curves. Single-gene GSEA further explored biological functions, and single-cell sequencing analysis was performed. Finally, the expression of hub genes and M1 macrophage markers (CD80/CD86) was experimentally validated in psoriasis mouse models. Results: Six hub genes (ISG15, RSAD2, IFIT3, OASL, GBP1, and IFIT1) were identified through cytoHubba algorithms. Functional enrichment analysis revealed significant associations between psoriasis-associated macrophage polarization and the RIG-I-like receptor, NOD-like receptor, and cAMP signaling pathways. Experimental validation verified the increased expression of these hub genes and M1 macrophage markers in LPS-stimulated RAW264.7 murine macrophages and IMQ-induced psoriasis animal models. Conclusion: Our findings suggest that six interferon-responsive genes (ISG15, RSAD2, IFIT3, OASL, GBP1, and IFIT1) could serve as potential biomarkers for M1 macrophage polarization in psoriasis. Targeting macrophage polarization through IFN pathway inhibition may offer novel therapeutic strategies, particularly for patients with prominent IFN signatures refractory to conventional treatments.