Recent studies have revealed the significant role of the competing endogenous RNA (ceRNA) network in human diseases. However, systematic analysis of the ceRNA mechanism in chronic rhinosinusitis with nasal polyps (CRSwNP) is limited. In this study, we constructed a competitive endogenous RNA (ceRNA) network and identified a potential regulatory axis in CRSwNP based on bioinformatics analysis and experimental verification. We obtained lncRNA, miRNA, and mRNA expression profiles from the Gene Expression Omnibus. After analysis of CRSwNP patients and the control groups, we identified 565 DE-lncRNAs, 23 DE-miRNAs, and 1799 DE-mRNAs by the DESeq2 R package or limma R package. Enrichment analysis of 1799 DE-mRNAs showed that CRSwNP was associated with inflammation and immunity. Moreover, we identified 21 lncRNAs, 8 miRNAs and 8 mRNAs to construct the lncRNA-miRNA-mRNA ceRNA network. A potential MIAT/miR-125a/IRF4 axis was determined according to the degree and positive correlation between a lncRNA and its competitive endogenous mRNAs. The GSEA results suggested that IRF4 may be involved in immune cell infiltration. The validation of another dataset confirmed that MIAT and IRF4 were differentially expressed between the CRSwNP and control groups. The area under the ROC curve (AUC) of MIAT and IRF4 was 0.944. The CIBERSORT analysis revealed that eosinophils and M2 macrophages may be involved in the CRSwNP process. MIAT was correlated with dendritic cells and M2 macrophages, and IRF4 was correlated with dendritic cells. Finally, to validate the key genes, we performed in-silico validation using another dataset and experimental validation using immunohistochemistry, immunofluorescence, and Western blot. In summary, the constructed novel MIAT/miR-125a/IRF4 axis may play a critical role in the development and progression of CRSwNP. We believe that the ceRNA network and immune cell infiltration could offer further insight into novel molecular therapeutic targets for CRSwNP.