Radiotherapy plays a crucial role in the multimodal treatment of breast cancer. However, radioresistance poses a significant challenge to its effectiveness, hindering successful cancer therapy. Emerging evidence indicates that Nrf2 and HIF-1 alpha are critical regulators of cellular anti-oxidant responses and that their overexpression significantly promotes radioresistance. Wogonin (WG), the primary component isolated from Scutellaria baicalensis, exhibits potential antitumor and reversal of multidrug resistance activities. Nevertheless, the role of WG in radioresistance remains unclear. This study aims to explore the effects of WG on the radioresistance of breast cancer. Our results indicate that Nrf2 and HIF-1 alpha overexpression was observed in breast cancer tissues and was correlated with the histological grading of the disease. Radiation further increased the levels of Nrf2 and HIF-1 alpha in breast cancer cells. However, WG demonstrated the ability to induce cell apoptosis and reverse radioresistance by inhibiting the Nrf2/HIF-1 alpha pathway. These effects were also confirmed in xenograft mice models. Mechanistically, WG enhanced the level of the Nrf2 inhibitor Keap1 through reducing CpG methylation in the promoter region of the Keap1 gene. Consequently, the Nrf2/HIF-1 alpha pathway, along with the Nrf2- and HIF-1 alpha-dependent protective responses, were suppressed. Taken together, our findings demonstrate that WG can epigenetically regulate the Keap1 gene, inhibit the Nrf2/HIF-1 alpha pathway, induce apoptosis in breast cancer cells, and diminish acquired radioresistance. This study offers potential strategies to overcome the limitations of current radiotherapy for breast cancer.