The purpose of this study was to study the mechanism of the increased sensitivity of breast cancer tamoxifen-resistant strains by enhancing ferroptosis. CCK-8 and colony formation were used to detect cell proliferation. Ferroptosis indicator reactive oxygen species (ROS), glutathione (GSH) activity, ATP activity, Fe content, and GPX4 protein expression were detected using ROS assay kit, reduced GSH content assay kit, ATP content assay kit, ferrous ion content assay kit, and western blotting, respectively. The protein levels of HO-1 and Nrf2-central regulators of antioxidant defense and ferroptosis resistance-were assessed by western blot. Tumor changes were observed in nude mice with subcutaneous tumorigenesis. Tamoxifen treatment reduced cell proliferation and colony formation, decreased GSH levels, and downregulated the expression of GPX4, Nrf2, and HO-1. Conversely, it increased ROS fluorescence intensity and Fe⁺ accumulation and impaired the formation of MCF-7 organoids. Overexpression of Nrf2 reversed the effect of tamoxifen. Compared with MCF-7 treated with tamoxifen, in MCF-7 TAMR treated with tamoxifen, the cell proliferation, clone number, ATP activity, and the mRNA expression of Nrf2 and HO-1 significantly increased. The subcutaneous tumor formation experiment in nude mice confirmed that tumors simultaneously treated with ML385 and tamoxifen can further shrink the tumor. The expression of Nrf2 in clinical breast cancer and recurrent breast cancer tissues was significantly higher than that in paracancerous and primary breast cancer tissues, respectively. ML385, the inhibitor of Nrf2, increased ferroptosis via inhibiting Nrf2/HO-1 pathway to enhance the sensitivity of MCF-7 TAMR to tamoxifen.