<p>Anaplastic thyroid carcinoma (ATC) remains one of the most lethal tumors, exhibiting a high recurrence rate, mortality rate and resistance to treatment. Post-translational modifications (PTMs) influence protein function by altering protein structure and play a crucial role in key signal transduction events related to tumor transformation and carcinogenesis, mainly including phosphorylation, ubiquitination, acetylation, and glycosylation. We highlight that dysregulation of PTM-mediated cascades in core proteins or signaling pathways serves as key factors in ATC progression. Phosphorylation, acetylation, and ubiquitination, along with the activation of various pathways, are associated with the proliferation, invasion, and metastasis of ATC. The first two PTMs significantly contribute to both targeted drug synthesis and the development of treatment resistance. Additionally, glycosylation is linked to the de-differentiation of ATC and offers an approach for new therapeutic strategies. Moreover, we discuss the potential of PTMs as biomarkers and therapeutic targets for ATC. Different PTMs play a crucial role in the application of various therapeutic approaches, particularly in the context of targeted drugs. These modifications underlie the molecular mechanisms for the selection of corresponding drugs and contribute to resistance. This review aims to provide a comprehensive understanding of the biological processes by which multiple PTMs co-regulate ATC by exploring the interplay of PTMs and their impact on ATC progression. Besides, there are still some gaps and unresolved issues in this field. By integrating different insights, we emphasize the progress in tools for early intervention to improve the prognosis of patients with ATC.</p>