Combination of chemotherapy and radiotherapy (chemoradiotherapy) can synergistically improve the cytotoxic action of chemotherapeutic agents while reducing their side effects. Gadolinium oxide nanoparticles (Gd2O3 NPs) have significant potential as radiosensitizer agents because of their distinctive properties. The surface modification of Gd2O3 NPs with PVP can increase their biocompatibility. The aim of this study was to evaluate the combination of Gd2O3 NPs as radiosensitizer and doxorubicin (DOX) as chemotherapeutic agent to improve cancer chemoradiotherapy. Doxorubicin loaded PVP-coated Gd2O3 NPs (Gd2O3@PVP-DOX NPs) were developed. MTT, and clonogenic assays showed that the viability and surviving fraction of B16F10 melanoma cells were significantly inhibited by treating with Gd2O3@PVP-DOX NPs under radiation compared with treating with the free DOX or PVP-Gd2O3 NPs alone under radiation. Furthermore, significant sensitization occurred with a maximum dose enhancement factor of 2.51 for Gd2O3@PVP-DOX NPs after irradiation. The radiosensitization activity of Gd2O3 NPs and more entrance and retention of DOX in the tumor cells after loading in Gd2O3@PVP-DOX NPs could cause effective inhibition of melanoma tumor cells growth and proliferation. In conclusion, the Gd2O3@PVP-DOX NPs developed in this study could represent a promising strategy for improved cancer chemoradiotherapy in melanoma.