Background: Prediction biomarkers associated with prognosis and lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) are needed to facilitate clinicians in choosing appropriate therapies.Objective: We hope to identify key genes associated with LNM and prognosis in PTC. Methods: GSE29265, GSE33630, GSE3467, GSE3678 and GSE58545 gene expression profiles were acquired from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between PTC tissues and normal thyroid tissues were selected with the GEO2R tool, and common DEGs among the five datasets were integrated with Venn software online. A proteinprotein interaction (PPI) network of the common DEGs was visualized. We analyzed the PPI network and determined core genes using the Cytoscape software. Furthermore, we employed UALCAN to verify the expression and promoter methylation status of the core genes in thyroid carcinoma (THCA). Additionally, the Kaplan–Meier plotter online tool was used to analyze the relationship between overall survival and core gene expressions in THCA. Results: TNS3, DUSP6, DUSP4 and PTPRE were identified as core genes. Expression of these 4 genes and the promoter methylation status of DUSP4 and PTPRE were strongly associated with LNM (P<0.05). High expression of 3 genes (DUSP6, DUSP4 and PTPRE) was related to a significantly better survival than low expression of the 3 genes in THCA. In contrast, high TNS3 expression was related to significantly worse survival (P<0.05). Conclusion: TNS3, DUSP6, DUSP4, PTPRE and DUSP4 and PTPRE promoter methylation status might be useful predictive biomarkers of LNM in PTC. Additionally, these genes may be prognostic biomarkers in PTC.