Objective To test the anticancer potential activity of the combination of thymoquinone (TQ) and resveratrol (RES) against breast cancer in mice. Methods The antiproliferative activity of TQ, RES and their combination was assessed against three breast cancer cell lines and one normal cells using MTT assay. The combination index was calculated using isobolographic method. Balb/C mice were inoculated with EMT6/P cells and in vivo antitumor activity was evaluated. Results The combination therapy also caused significant decrease in tumor size with a percentage cure of 60%. The combination therapy induced geographic necrosis, enhanced apoptosis, and decreased VEGF expression. Serum levels of IFN-γ were elevated in mice treated with combination therapy with no liver or kidney toxicity. Conclusions The combination of TQ and RES against breast cancer in mice can work synergistically. The anticancer effect of this combination is mediated by apoptosis induction, angiogenesis inhibition and immune modulation.