The proto‐oncogene c‐Myc has a pivotal function in growth control, differentiation, and apoptosis and is frequently affected in human cancer, including breast cancer. Ubiquitin‐specific protease 22 (USP22), a member of the USP family of deubiquitinating enzymes (DUBs), mediates deubiquitination of target proteins, including histone H2B and H2A, telomeric repeat binding factor 1, and cyclin B1. USP22 is also a component of the mammalian SAGA transcriptional co‐activating complex. In this study, we explored the functional role of USP22 in modulating c‐Myc stability and its physiological relevance in breast cancer progression. We found that USP22 promotes deubiquitination of c‐Myc in several breast cancer cell lines, resulting in increased levels of c‐Myc. Consistent with this, USP22 knockdown reduces c‐Myc levels. Furthermore, overexpression of USP22 stimulates breast cancer cell growth and colony formation, and increases c‐Myc tumorigenic activity. In conclusion, the present study reveals that USP22 in breast cancer cell lines increases c‐Myc stability through c‐Myc deubiquitination, which is closely correlated with breast cancer progression. The present study reveals that deubiquitinating enzyme USP22 in mammalia and breast cancer cell lines increases c‐Myc stability through c‐Myc deubiquitination, which is closely correlated with breast cancer progression.