Krüppel-like factor 4 (KLF4) is an important transcription factor implicated in a variety of essential cellular processes. Aberrant KLF4 expression is closely related to tumourigenesis and tumour progression. The rapid turnover of the KLF4 protein indicates an important role for the posttranslational modifications (PTMs) of KLF4. To date, E3 ligases mediating KLF4 ubiquitination have been widely reported, yet the deubiquitinating mechanism of KLF4 remains largely unknown. We screened a library of 65 deubiquitinating enzymes and identified ATXN3 as a deubiquitinating enzyme of KLF4. Subsequent immunoprecipitation assays confirmed that ATXN3 bound to KLF4, mediating the deubiquitination and stabilization of KLF4 protein levels. Furthermore, we demonstrated that ATXN3 promoted breast cancer cell metastasis via KLF4 in vitro and in vivo. Finally, the protein expression analysis of human breast cancer specimens demonstrated that ATXN3 significantly correlated with KLF4. High ATXN3/KLF4 expression was associated with a poor prognosis in breast cancer patients. Collectively, we identified ATXN3 as a novel deubiquitinating enzyme of KLF4, providing a new explanation for breast cancer metastasis, and proposed ATXN3 as a potential target for breast cancer metastasis treatment.