Cerium oxide nanoparticles (nanoceria) have been shown to protect cells against oxidative stress in both cell culture and animal models. Their superoxide dismutase (SOD) mimetic activity is believed to be responsible for this protection. This study confirms nanoceria's reactivity as an SOD mimetic using electron paramagnetic resonance (EPR) analysis. X-ray photoelectron spectroscopy (XPS) and UV-visible analysis show that a decrease in the Ce³+/⁴+ ratio correlates with a loss of SOD mimetic activity. These results suggest that the surface oxidation state of nanoceria plays a key role in its SOD mimetic activity, with the ability to scavenge superoxide directly related to cerium (III) concentrations at the particle surface. Cerium exists in multiple oxidation states, with Ce³+ and Ce⁴+ absorbing ultraviolet light and having characteristic spectrophotometric peaks. Nanoceria has unique catalytic properties due to oxygen vacancies on its surface, which are surrounded by Ce³+ and Ce⁴+ atoms. These vacancies are thought to be responsible for the altered redox chemistry of nanoceria compared to bulk cerium. Nanoceria is being explored for various applications, including catalytic converters, carbonic anhydrase inhibitors, and oxygen sensors. It has also been tested in animal and cell culture models for its ability to protect against oxidative stress. Studies show that nanoceria reduces oxidative stress in neuronal cells and decreases cellular senescence in rat neurons. Transgenic mice treated with nanoceria showed reduced inflammation and cell death in a cardiovascular disease model. The protective effects of nanoceria are attributed to its radical scavenging capabilities, with SOD mimetic activity being the only specific activity reported. This study further explores the mechanism behind this activity, focusing on the Ce³+/⁴+ ratio at the particle surface. EPR analysis confirmed that nanoceria catalyzes SOD activity and is specific for superoxide radicals. XPS analysis showed that hydrogen peroxide oxidizes the surface of nanoceria from Ce³+ to Ce⁴+, reducing its SOD mimetic activity. UV-visible spectrophotometry confirmed this oxidation, showing an increase in Ce⁴+ and a decrease in Ce³+ after hydrogen peroxide treatment. The SOD mimetic activity of nanoceria was tested using a ferricytochrome C assay. Hydrogen peroxide-treated nanoceria lost nearly all detectable SOD mimetic activity within 48 hours but regained nearly 100% of the original activity over the following 14 days. This suggests that hydrogen peroxide temporarily inactivates the SOD mimetic activity of nanoceria, which is transient as the peroxide decomposes. The return of SOD mimetic activity was accompanied by a corresponding drop in absorbance at 300–400 nmCerium oxide nanoparticles (nanoceria) have been shown to protect cells against oxidative stress in both cell culture and animal models. Their superoxide dismutase (SOD) mimetic activity is believed to be responsible for this protection. This study confirms nanoceria's reactivity as an SOD mimetic using electron paramagnetic resonance (EPR) analysis. X-ray photoelectron spectroscopy (XPS) and UV-visible analysis show that a decrease in the Ce³+/⁴+ ratio correlates with a loss of SOD mimetic activity. These results suggest that the surface oxidation state of nanoceria plays a key role in its SOD mimetic activity, with the ability to scavenge superoxide directly related to cerium (III) concentrations at the particle surface. Cerium exists in multiple oxidation states, with Ce³+ and Ce⁴+ absorbing ultraviolet light and having characteristic spectrophotometric peaks. Nanoceria has unique catalytic properties due to oxygen vacancies on its surface, which are surrounded by Ce³+ and Ce⁴+ atoms. These vacancies are thought to be responsible for the altered redox chemistry of nanoceria compared to bulk cerium. Nanoceria is being explored for various applications, including catalytic converters, carbonic anhydrase inhibitors, and oxygen sensors. It has also been tested in animal and cell culture models for its ability to protect against oxidative stress. Studies show that nanoceria reduces oxidative stress in neuronal cells and decreases cellular senescence in rat neurons. Transgenic mice treated with nanoceria showed reduced inflammation and cell death in a cardiovascular disease model. The protective effects of nanoceria are attributed to its radical scavenging capabilities, with SOD mimetic activity being the only specific activity reported. This study further explores the mechanism behind this activity, focusing on the Ce³+/⁴+ ratio at the particle surface. EPR analysis confirmed that nanoceria catalyzes SOD activity and is specific for superoxide radicals. XPS analysis showed that hydrogen peroxide oxidizes the surface of nanoceria from Ce³+ to Ce⁴+, reducing its SOD mimetic activity. UV-visible spectrophotometry confirmed this oxidation, showing an increase in Ce⁴+ and a decrease in Ce³+ after hydrogen peroxide treatment. The SOD mimetic activity of nanoceria was tested using a ferricytochrome C assay. Hydrogen peroxide-treated nanoceria lost nearly all detectable SOD mimetic activity within 48 hours but regained nearly 100% of the original activity over the following 14 days. This suggests that hydrogen peroxide temporarily inactivates the SOD mimetic activity of nanoceria, which is transient as the peroxide decomposes. The return of SOD mimetic activity was accompanied by a corresponding drop in absorbance at 300–400 nm