Papillary Thyroid Cancer (PTC) is one of the most prevalent endocrine malignancies, and its incidence rate has almost tripled over the past three decades. The current study aimed to identify gene alterations and biomarkers contributing to PTC progression. Based on PTC transcriptome sequencing data, differential gene expression analysis is used to systematically categorize hub genes associated with PTC progression. A total of 1550 overlapping differentially expressed genes (DEGs) were identified in PTC compared to normal thyroid tissues, including 1149 upregulated and 401 downregulated genes. In addition, 3,192 DEGs were detected in PTC relative to their normal adjacent tissues (NATs), comprising 1,431 upregulated and 1,761 downregulated genes. KEGG pathway analysis revealed pathways associated with cancer, proteoglycans in cancer, parathyroid hormone synthesis, and chemical carcinogenesis receptor activity. Protein-protein interaction (PPI) network analysis identified FN1, SDC1, and MAPK1 as highly ranked hub genes among the upregulated genes involved in several cancer pathways, including the PID Syndecan-1 pathway, Proteoglycans in cancer, and the CCL18 signaling pathway. The gene expression validation through Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) further validated the significance of the above findings, demonstrating substantial upregulation of FN1 (7.4-fold increase), SDC1 (5.2-fold increase), and MAPK1 (5.8-fold increase) in papillary thyroid tissues relative to their adjacent normal tissues. Western blot analysis further validated the upregulation of FN1 at the protein level. These findings highlight a strong association between the identified hub genes (FN1, SDC1, and MAPK1) and papillary thyroid cancer, supporting their potential as diagnostic biomarkers and therapeutic targets. Further validation through in vivo experiments and functional assays will be essential to confirm their roles in PTC pathogenesis and to elucidate their clinical implications.