Breast cancer is a malignant disease and a great cause of morbidity and mortality in women. The etiology of breast cancer is complex and closely related to people's living habits. Lapatinib, a tyrosine-kinase inhibitor, blocks the activation of the HER1 and HER2 tyrosine kinase to inhibit the activation of downstream signaling pathways and thus inhibit tumor survival and proliferation. This study aimed to explore to the combination of lapatinib and luteolin on human breast cancer. The combination of lapatinib and luteolin increased the sensitivity of SKBR-3, BT-474 and ZR-75-1 cells. This combination equally up-regulated the expression of FOXO3a and NQO1 and their downstream target genes Bim, GADD45, P21, and the phosphorylation level of FOXO3a protein decreased. The mice transplanted with BT-474 cells, the volume of subcutaneous tumors in the luteolin group, lapatinib group, and lapatinib + luteolin group were significantly smaller than the control group. The results of Western blot showed that in tumor tissues of mice transplanted with BT-474 cells, the expression levels of FOXO3a and NQO1 protein in the luteolin group, lapatinib group, and lapatinib + luteolin group were all obviously upregulated, the mice transplanted with ZR-75-1 cells exhibited similar results. These data suggest that the combination of lapatinib and luteolin may inhibit HER2+ human breast cancer by significantly increasing the expression of FOXO3a and NQO1, two key genes in HER2+ human breast cancer xenografts. (c) 2020 Elsevier Inc. All rights reserved.