Introduction: Thyroid cancer is the most common endocrine cancer. The study of the signaling pathways involved in thyroid cancer, such as PI3K/AKT/mTOR and their driver mutations, has significantly improved the understanding of the molecular pathogenesis of thyroid cancer. Consequently, targeted therapies have been developed using tyrosine kinase receptors and cascade proteins inhibitors. Materials and Methods: PubMed database and Science Direct website were searched to investigate the alterations in this signaling pathway in thyroid cancer from January 2016 to January 2023. Articles related to clinical symptoms, conventional treatments, histopathology, and diagnostic tests, as well as reports, letters to the editor, results of confer­ences, and annual meetings, were excluded from the study. Then the remaining articles were carefully studied. Keywords included thyroid neoplasm, thyroid carcinoma, thyroid cancer, and PI3K. Results: Somatic mutations and increased expression of the PIK3CA gene, the mutations in PTEN tumor suppressor gene, RAS, BRAF, and RET proto-oncogene mutations, CTNNB1 and EIF1AX gene mutations, RET/PTC, PAX8/PPARγ, and NTRK rearrangements, as well as AKT mutations and rearrangements, were the most important alterations that increased the expression of PI3K/AKT pathway proteins. This pathway and its connections with other signaling pathways were one of the leading reasons for the development and recurrence of thyroid cancer. Conclusion: Understanding the intracellular network of signaling pathways based on tyrosine kinase receptors, such as PI3K, and their cross-talk in physiological and pathological conditions, as well as their driver mutations, are the goal of research in recent years to develop combination therapies using inhibitors of these pathways.