Multikinase inhibitors (MKIs) and highly selective tyrosine kinase inhibitors (HS-TKIs) positively impact the progression-free survival (PFS) of locally advanced and metastatic thyroid cancer cases. Moreover, disease-specific survival (DSS) and overall survival (OS) improvements were observed in some instances, suggesting a general benefit in disease control. In advanced and metastatic thyroid cancers, other conventional treatments are often ineffective when surgery cannot be performed due to the extension of the disease and/or the invasion of vital neck structures (such as the larynx, trachea, esophagus, recurrent laryngeal nerve, and carotid artery). In these cases, systemic treatments with MKIs and HS-TKIs have recently been evaluated for their potential to block tumor growth and reduce tumor size to make surgery possible or improve the control of metastatic disease. The study aimed to evaluate the performance of these systemic drugs in the neoadjuvant treatment of thyroid cancer patients, focusing on their efficacy according to the different histology.