Background: The most typical endocrine cancer is thyroid cancer. Tumor biomarkers are genetic or protein-level compounds or specific evaluable traits. They assist in improving patient management. The goal of this study was to assess the ability of individual and combined potential markers (hyaluronic acid (HA), nuclear matrix protein (NMP-1), and angiopoietin-1) for thyroid cancer diagnosis.  Patients and methods:  This study registered 145 people (n=145), including 60 thyroid cancer, 65 benign group and 20 healthy controls.  According to fine-needle aspiration (FNA) biopsy, Histopathological findings were divided into benign and thyroid cancer groups. The latter was further staged using the TNM approach, where (T) stands for tumor size and local invasion, (N) for nodal metastases, and (m) for distant metastases. We used biochemical routine profile tests like Total triiodoyhyronine (T3), Total thyroxine (T4), free Triiodothyronine (FT3), Free thyroxine (FT4), and thyroid-stimulating hormone (TSH). These measurements were done using Mini Vidas, Biomerieux, and ST-200 plus electrolyte analyzer (ELFA). We also measured HA, NMP-1 and ANG-1 by using Sandwich Enzyme-Linked Immunosorbent Assay (ELISA) technique .Results: The diagnostic performances of single and combined markers were evaluated using area under Roc curve. An area under the Roc curve of 0.81, 0.62, and 0.67, respectively, was observed for hyaluronic acid, NMP, and ANG. The best marker for identifying thyroid is HA, A three-marker index called thyroid markers (hyaluronic acid, NMP, ANG) was developed. The thyroid mark's diagnostic performance at a selected cutoff index of 6.2. The thyroid marker's AUC was 0.87, its sensitivity was 86%, and its specificity was 80% when it came to distinguishing thyroid cancer from benign conditions. When distinguishing thyroid cancer from healthy individuals, the thyroid mark's AUC was 0.96, its sensitivity was 96%, and its specificity was 100%. Conclusion: HA, NMP-1 and ANG-1 are effective biomarkers to distinguish between thyroid cancer and benign with acceptable sensitivity and specifity.