The present study evaluates the prophylactic efficacy of alpha-tocopherol (alpha-TOH), resveratrol (RES), and coenzyme Q10 (CoQ10) co-loaded self-nanoemulsifying drug delivery system (alpha-TOH-RES-CoQ10 SNEDDS) in 7,12-Dimethylbenz[a]anthracene (DMBA) induced breast cancer model. SNEDDS formulation components were rationally selected and optimized for maximum drug loading by applying the design of experiments and further evaluated for stability in simulated gastrointestinal fluids, functional stability of antioxidants, in vitro release, Caco-2 cell uptake, oral bioavailability and prophylactic anticancer activity. The SNEDDS demonstrated excellent stability in stimulated gastrointestinal fluids. The functional activity of antioxidants was confirmed by 2,2-diphenylpicrylhydrazyl (DPPH) scavenging assay wherein significantly (p>. 05) higher antioxidant activity was observed in case of SNEDDS as compared with free antioxidants. Coumarin 6 (C-6)-loaded SNEDDS formulation demonstrated remarkably higher Caco-2 cell uptake in comparison with free C-6, indicative of efficient internalization of sub-micron SNEDDS droplets by Caco-2 cells. In line with Caco-2 cell uptake observations, alpha-TOH-RES-CoQ10-SNEDDS showed similar to 2.30- and similar to 3.64-fold increase in the AUC(0-infinity) values of RES and CoQ10 in comparison with free antioxidants. Significantly lower (p<. 001) tumor volume (similar to 327mm(3)) was found in case of animals treated with alpha-TOH-RES-CoQ10-SNEDDS in comparison with free antioxidant combination (similar to 1070mm(3)) and DMBA control (similar to 1540mm(3)) groups. Conclusively, the proposed strategy posed great potential in improving the prophylactic activity of antioxidants and hold promise for further exploration.