Abstract Background: There is an ongoing need for targeted therapy and systemic treatment protocols for papillary thyroid carcinoma (PTC) patients. Yes activated protein-1 (YAP-1) has been found to control many targets of Hippo pathway. Annexin family is a huge family playing many roles in cellular processes. Annexin A10 (ANXA10) is a member of annexin family. Uncoordinated-5D (UNC5D), a recently discovered Unc5 family member which is found in normal tissues and downregulated in cancer cell lines and tissues. Aim of the study was to assess the expression of YAP-1, ANXA10, and UNC5D in PTC and in non-neoplastic tissues of thyroid gland using immunohistochemistry to evaluate their clinical significance and prognostic values in PTC patients. Method: In the present prospective study, we took samples from 60 patients with PTC and 30 samples from non-neoplastic thyroid tissues for YAP-1, ANXA10, and UNC5D immunohistochemistry. All the patients were followed up for assessment of the prognostic, clinical, and pathological of their expression. Results: Upregulation of YAP-1 and ANXA10 in addition to downregulation of UNC5D was found in PTC tissues more than non-neoplastic thyroid tissues. In PTC tissues, there were positive associations between high YAP-1 and ANXA10 expression, low UNC5D expression, tumor size (P = 0.022, 0.011, 0.014), presence of lymph node metastases (P = 0.005, < 0.001, 0.008), and inferior disease-free survival rate (P = 0.003, 0.01, 0.03). Conclusion: Upregulation of YAP-1 and ANXA10 expression and downregulation of UNC5D was associated with bad clincopathological criteria, disease progression, high incidence of disease recurrence, and poor survival.