Ataxin-3 (ATXN3) is a ubiquitous deubiquitinating enzyme that plays an essential role in the carcinogenesis of numerous tumors and stabilizes the expression of substrates by deubiquitination. However, the functional role of ATXN3 in anaplastic thyroid carcinoma (ATC) remains unknown. In this research, we report that ATXN3 was overexpressed in ATC compared to that in paracancerous samples. Moreover, various gain/loss functional assays were performed to indicate that ATXN3 overexpression enhanced ATC cell proliferation and metastasis. We also found that ATXN3 and eukaryotic translation initiation factor 5A2 (EIF5A2) protein levels in ATC tissues are positively correlated, and ATXN3 promotes the proliferation and metastasis of ATC cells through EIF5A2. Mechanistically, ATXN3 promotes EIF5A2 expression by directly binding to EIF5A2 to reduce its ubiquitination and degradation. Therefore, for the first time, we clarified the role of ATXN3 in the carcinogenesis of ATC cells, which provides novel insights into potential therapeutic targets for ATC progression.