Nanoparticulate chemotherapeutics hold great potential for inducing reactive oxygen species (ROS) overproduction and exerting antihypoxic effects for efficient cancer radiotherapy. However, previous strategies for designing smart radiosensitizers necessitate the multistep incorporation of nanomaterials to achieve valuable radiosensitive outcomes, which causes unpredictable safety issues including poor decomposition and undefined biotransformations. Ultrathin antimonene nanoparticles (AMNPs) are demonstrated as new radiosensitizers that achieve an efficient radiochemotherapeutic effect through the induction of a strong oxidative stress response and their significantly high radiotoxicity in vivo. Analyzing the irradiation process of AMNPs indicates that irradiation accelerates photoelectron generation and the valence transition to toxic Sb2O3, leading to cancer cell apoptosis and S‐phase arrest. The tumor regression activity and concealed biotoxicity of the AMNPs in a melanoma mouse model enhance the applicability of antimonene to overcoming radioresistance by increasing ROS generation and normoxia. This new technology can extend the applications of antimonene as an effective radiosensitizer and can promote its clinical translation for tunable and effective radiosensitization in the future.