In the study, we probed into the effect of Resveratrol (RES) on Doxorubicin (DOX)-resistant breast neoplasm cell line MCF-7/DOX as well as the mechanism of RES underlying the DOX-resistant breast cancer. CCK-8 assay was utilized to assess the survival rates and sensitivity of breast neoplasm cell lines MCF-7 or MDA-MB-231 to DOX and RES. DOX-resistant MCF-7 cell line was successfully cultivated with DOX dose increasing and was named MCF-7/DOX. Afterwards, wound healing and Transwell assays were performed to measure the migration and invasion capabilities of MCF-7/DOX cells, while cell propagation and apoptosis were determined by colony formation assay and flow cytometry analysis. Both western blotting and immunohistochemistry were conducted to examine the expression of proteins involved in PI3K/Akt signaling pathway. Nude mice xenograft model was constructed to further verify the effects of DOX and RES on breast neoplasm in vivo. RES restored DOX sensitivity in MCF-7/DOX cells, inhibiting biological functions of MCF-7/DOX cells and promoting cell apoptosis in vitro and impeding tumor growth in vivo. It was revealed by the mechanistic studies that MCF-7/DOX cells could regain the drug sensibility with RES treatment through inactivating the PI3K/Akt signal transduction pathway. RES could reverse DOX resistance in breast neoplasm cells and inhibited DOX-resistant breast cancer cell propagation and metastasis and facilitated cell apoptosis by modulating PI3K/Akt signaling pathway. (c) 2018 IUBMB Life, 70(6):491-500, 2018