Breast cancer is a heterogenous group of malignant tumors which is the most common cancer that affected women worldwide. Despite radiotherapy considered as one of the most major strategies for cancer treatment, but it is still limited due to the developed resistance by highly metastatic cancers. This study is designed to assessment the anti-cancer characteristics and radio-sensitizing effect of Indole-3-carbinol (I3C) and Resveratrol (RES) on MDA-MB-231 cells. the effective dose of I3C and RES that will be used as a radio-sensitizing dose was assessed using MTT assay. Treatment of MDA-MB-231 cells with I3C+ RES, and/or ionizing radiation (IR) led to significant downregulation at cell proliferation as indicated by the decreased of developed colony ratio. The combined therapy induced apoptosis by which was indicated by the significant increase of Bax and downregulation of Bcl-2 level expression. Combined treatment significantly attenuated MDA-MB-231 cells motility which was validated using wound healing assay after 24hr of pretreatment. Combined treatment revealed a significant reduction at Nrf2 level which in turn leads to downregulation at both anti-oxidant enzymes Catalase and Glutathione Synthesis. the pretreatment with I3C+ RES, and/or IR revealed a significant decrease on e-cadherin, and elevation at vimentin level expression. This study assesses the anti-cancer effect of I3C plus RES, by its important role in spectacular cell responsiveness to IR leading to a significant inhibition at MDA-MB-231 cell proliferation, migration and survival.