Objective(s): Cerium oxide nanoparticles (Ceo(2) NPs) are considered one of the most effective nanomaterials for drug delivery. The current study aimed to investigate the anticancer activities of doxorubicin-loaded Ceo(2) NPs (DOX-Ceo(2) NPs) against the MDA-MB-231 human breast cancer cell line. Materials and Methods: Ceo2 NPs were synthesized using the GREEN synthesis method and loaded with DOX (DOX-Ceo(2) NPs). The physicochemical properties of the Ceo(2) NPs were evaluated using FTIR, XRD, DLS, zeta potential, and electron microscopy (SEM/TEM). Cultured MDA-MB-231 cells were treated with different concentrations of bare Ceo(2) NPs, free DOX, and DOX-Ceo(2) NPs. In addition, HDF cells were treated with different concentrations of Ceo(2) NPs. MTT, wound healing, and flow cytometry assays were performed to determine the cell viability, migration, and apoptosis, respectively. qPCR was performed to investigate the expression of genes involved in apoptosis, including caspase (CASP) 3, 8, 9, and Bcl-2. Results: The XRD and FTIR results confirmed the synthesis of pure and crystalline structured- Ceo(2) NPs. The average size, PDI, and zeta potential of the Ceo(2) NPs were approximately 239.1 nm, 0.074, and-9.04 mV, respectively. In vitro assays showed that DOX-Ceo(2) NPs exhibited higher cell proliferation inhibition, migration suppression, and apoptosis induction through the upregulation of CASP3, CASP8, and CASP9 genes and downregulation of Bcl-2. Conclusion: Our data demonstrate the potential of Ceo(2) NPs for the efficient delivery of DOX and, subsequently, the improvement of its anticancer activities. Therefore, DOX-Ceo(2) NPs have the potential to be as anticancer for breast cancer.