The pathogenesis of papillary thyroid cancers (PTCs) is complex and not fully known yet. Cervical lymph node metastasis (CLNM) is associated with increased risk of recurrence and poor prognosis. The present study aimed to identify differentially expressed proteins (DEPs) associated with PTC-CLNM for monitoring invasive PTC progression. We employed 4D mass spectrometry (MS) to identify DEPs of cancer and serum samples in PTC patients combined with or without CLNM. The functional annotation of DEPs was performed using bioinformatics methods including annotation methods, functional enrichment, enrichment-based clustering and protein-protein interaction network. In total, we identified 21 and 17 proteins that were significantly differentially expressed between PTC-CLNM and PTC-NCLNM (PTC-non cervical lymph node metastasis) in tissue and serum samples, respectively. Comparative analyses revealed that DEPs including NGFR, PBXIP1, HSP90B1, CD44, NFIA, PFKP and SRGN were associated with tumor metastasis. A number of proteins were identified that may be relevant to tumor growth and metastasis, and this provides an opportunity for future functional proteomics studies and to investigate potential biomarkers predicting PTC-CLNM.