We investigated the role of chrysin as an effective adjuvant along with nanostructured lipid carriers (NLCs) to increase the cytotoxicity of doxorubicin (Dox) in MCF-7 breast cancer cells. The prepared formulation was characterized from point of view scanning electron microscope (SEM), size & zeta potential. Cellular uptake and cytotoxicity of nanoparticles were examined by fluorescent microscopy and MTT assay, respectively. Flow cytometry and real-time PCR were used to understand the molecular mechanism of Nrf2 and related downregulating genes. The average size of the nanoparticles was 105 +/- 2 nm, which was confirmed by SEM. Our results demonstrated that incubation of the cells with chrysin-loaded NLCs enhanced the percentage of apoptosis from 21.11 +/- 5.72% to 27 +/- 3.13% (p < 0.05). Furthermore, the population of cancer cells in the sub-Gi phase increased up to 12 +/- 2.1% compared to untreated cells (p < 0.05). mRNA expression levels of Nrf2, NQO1, 1101, and MRP1 exhibited a significant decrease compared to the control group (p < 0.05). Our findings recommend that chrysin delivery along with NLCs would enhance the efficacy of Dox by exerting inhibitory effects against drug efflux pumps and drug detoxification enzymes.