Tamoxifen (TMX) is widely employed in the treatment of breast cancer. However, owing to its poor solubility (BCS class II drug), rapid first-pass metabolism and free radical generation leading to hepatotoxicity, a better drug delivery platform is required. A sufficient concentration of TMX must be achieved while avoiding harm to healthy cells in the target for effective therapy. Carvacrol (CV), a natural monoterpene, has reported antitumor activity and cell growth inhibition effects on MCF-7 and MDA-MB-231 breast cancer cells. In the current study, TMX and CVR-loaded nano-emulsion was prepared and incorporated into thermosensitive poloxamer gel to achieve enhanced anticancer action locally. Box-Behnken Design was employed to extensively optimize the prepared formulation wherein the droplet size obtained was 97.53 ± 1.80 nm and PDI was 0.195 ± 0.0026. The developed thermogel was characterized for gelation temperature, rheology, hemolysis and drug release. The gelation and higher viscosity were attended closer to body temperature (37 ± 0.5 °C), and showed retarded drug release (∼60 % after 5 days). The developed thermogel showed 16.02 % hemolysis as compared to 71.89 % from free TMX. Further, In-vitro cell culture studies of the developed formulation revealed significantly enhanced cytotoxicity and almost 6-fold higher cellular internalization. In addition, dose-dependent lowering of mitochondrial membrane potential and 5.9-fold higher ROS production by TMX-CVR-NE was observed. Therefore, an in-situ thermo-gel depot of TMX and CVR imparted an attractive way for the controlled delivery and enhanced local activity of TMX in breast cancer.