Breast cancer is the most frequently diagnosed cancer in both more and less economically developed countries and remains the leading cause of cancer-related death in women worldwide. In this study, to explore the expression and pathological role of RSK4 in breast cancer progression, we demonstrated that RSK4 expression was significantly decreased in breast cancer cells and tissues, and the overexpression of RSK4 in MDA‑MB‑231 cells inhibited cell migration and invasion. In a mouse model experiment, overexpression of RSK4 in mice further confirmed its critical role in regulating breast cancer tumorigenicity. The regulatory role of RSK4 in breast cancer development was mediated by AKT and extracellular signal‑regulated kinase (ERK) signaling pathways and the expression of RSK4 was altered by DNA methylation in promoter regions. These results provide important insight into the role of RSK4 in cancerogenesis and may help to improve the prevention, diagnosis and treatment of breast cancer.