Thyroid cancer is the most frequent endocrine malignancy and accounts for approximately 1% of all diagnosed cancers. A variety of mechanisms are involved in the transformation of a normal tissue into a malignant one. Loss of tumor-suppressor gene (TSG) function is one of these mechanisms. The normal functions of TSGs include cell proliferation and differentiation control, genomic integrity maintenance, DNA damage repair, and signaling pathway regulation. TSGs are generally classified into three subclasses: (i) gatekeepers that encode proteins involved in cell cycle and apoptosis control; (ii) caretakers that produce proteins implicated in the genomic stability maintenance; and (iii) landscapers that, when mutated, create a suitable environment for malignant cell growth. Several possible mechanisms have been implicated in TSG inactivation. Reviewing the various TSG alteration types detected in thyroid cancers may help researchers to better understand the TSG defects implicated in the development/progression of this cancer type and to find potential targets for prognostic, predictive, diagnostic, and therapeutic purposes. Hence, the main purposes of this review article are to describe the various TSG inactivation mechanisms and alterations in human thyroid cancer, and the current therapeutic options for targeting TSGs in thyroid cancer.