Nanomaterials with antioxidant properties are promising for treating reactive oxygen species (ROS)‐related diseases. However, maintaining efficacy at low doses to minimize toxicity is a critical for clinical applications. Tuning the surface strain of metallic nanoparticles can enhance catalytic reactivity, which has rarely been demonstrated in metal oxide nanomaterials. Here, it is shown that inducing surface strains of CeO2/Mn3O4 nanocrystals produces highly catalytic antioxidants that can protect tissue‐resident stem cells from irradiation‐induced ROS damage. Manganese ions deposited on the surface of cerium oxide (CeO2) nanocrystals form strained layers of manganese oxide (Mn3O4) islands, increasing the number of oxygen vacancies. CeO2/Mn3O4 nanocrystals show better catalytic activity than CeO2 or Mn3O4 alone and can protect the regenerative capabilities of intestinal stem cells in an organoid model after a lethal dose of irradiation. A small amount of the nanocrystals prevents acute radiation syndrome and increases the survival rate of mice treated with a lethal dose of total body irradiation.