Abstract: Thyroid cancer is a common malignancy of the endocrine system. Patients in advanced stage, with radioactive iodine-refractory, and anaplastic thyroid cancer have an extremely poor prognosis, and clinical treatment options are limited. Targeted therapy is a crucial therapeutic approach for thyroid cancer. However, drug resistance significantly compromises its clinical efficacy and prognosis. The targeted drug resistance of thyroid cancer involves multiple pathophysiological mechanisms, in which the dysregulated dynamic interplay between epigenetic reprogramming and the immune microenvironment plays a pivotal role. Specifically, mechanisms such as RNA modifications, DNA methylation, and histone modifications synergistically promote the development of drug resistance by modulating alternative splicing reprogramming and immune checkpoint expression. This article reviews the molecular mechanisms underlying targeted drug resistance in thyroid cancer, focusing on the interplay between epigenetic modifications and the immune microenvironment, aiming to provide a reference for overcoming the limitations of monotherapy.