As the most common malignant tumor, the incidence of papillary thyroid carcinoma (PTC) has been significantly increased over the past few years. Approximately 30%-90% of patients with PTC present with cervical lymph node metastasis (LNM) at the time of initial diagnosis or follow-up, which has a serious impact on survival and prognosis. Six PTC N0 samples and six PTC N1b samples were collected. Proteins from the samples were analyzed by label-free quantitative proteomics. The bioinformatics of differentially expressed proteins (DEPs) was annotated with bioinformatic tools. The protein expression levels of the hub genes were verified using the HPA databases. Finally, we used the GEPIA database to perform survival analysis for the hub genes. A total of 1407 proteins were quantified under highly stringent criteria with fold change ≥ 2.0 and P < 0.05, and 95 DEPs were significantly changed between groups. Identified from the Cytoscape, the top 10 hub genes included FN1、CFL1、LGALS3、ANXA1、TIMP1、TPI1、MAPK1、HSPA9、ACTR2 and S100A11. We determined the hub genes expression in thyroid normal and cancer tissues using the HPA database. The expression of FN1 and ANXA1were closely related to disease free survival (DFS) and overall survival (OS) prognosis in PTC patients based on GEPIA database. These results revealed the pathways and mechanisms of LNM in PTC, thus providing a new perspective for the study of PTC with LNM. Together, these hub genes may have some clinical value in diagnosing PTC patients with LNM.