Investigations of the molecular mechanisms underlying the metastatic phenotype of papillary thyroid cancer (PTC) and identification of novel candidate biomarkers to better predict PTC metastasis are urgently required. Tandem mass tag-based quantitative proteomics approach is used to identify differentially expressed proteins (DEPs) in PTC tumorous tissues with different degrees of lymph node metastases (LNMs). Furthermore, DEPs and their clinical significance are analyzed in another independent Cancer Genome Atlas dataset. The protein profiles among tumorous tissues with different degrees of LNMs are clearly distinguished, while the protein profiles in normal tissues are remarkably similar. DEPs in tumorous tissues are mostly enriched in the categories associated with pathological hallmarks of cancer, including extracellular matrix, metabolism, and cell growth. The expression patterns of six DEPs (LAMC2, LAMB3, ATP5A1, MYO1G, S100A4, and FAS) are confirmed by the Cancer Genome Atlas dataset. Additionally, the elevated expression of LAMC2 and MYO1G mRNA levels in tumorous tissues show a positive relationship with unfavorable variables, including larger tumor size, LNMs, high AJCC staging, BRAFV600E mutation, and poor prognosis. LAMC2 and MYO1G are identified as potential candidate biomarkers for the prediction of PTC metastasis and prognosis. © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.