Abstract It is important to detect novel predictive biomarkers of cervical lymph node metastasis (CLNM) in papillary thyroid carcinoma (PTC) to help the surgeons in making early decision of performing central lymph node dissection and aggressive management strategies in selected high-risk patients, thus improving their prognosis. Zinc finger protein 703 (ZNF703) is a member of the neutrophil extracellular trap (NET) transcription factors family which has roles in proliferation and invasion of cancer cells. SMAD4 is a protein that has a role in cellular processes including cell proliferation, invasion, and metastasis through many genes’ transcription. In this study, we aimed to assess the expression of ZNF703 and SMAD4 in PTC and evaluated the correlation between its expression, clinicopathological features of PTC cases, and prognostic parameters of patients to evaluate their roles in PTC progression. This is a retrospective study which included 40 cases with PTC. For immunohistochemistry, tissues stained their paraffin blocks with ZNF703 and SMAD4. We followed patients to detect disease progression and recurrence. Positive ZNF703 expression and negative SMAD4 expression were associated with higher incidence of CLNM, advanced stage and large tumor size, higher incidence of disease progression, recurrence, unfavorable PFS, and unfavorable OS rates. The higher ZNF703 expression and the lower SMAD4 expression were significantly increased in PTC patients with cervical LNM compared with those without. ZNF703 over expression and downregulation SMAD4 expression was significantly increased in PTC patients. Elevated expression of ZNF703 in tumor tissue with CLNM can be considered a predictive factor for the development of metastasis.