Nanozyme materials open up new opportunities in reactive oxygen species (ROS)-related heart diseases. However, the development of a stable and efficacious nanozyme for treating cardiac injuries remains a significant challenge. Herein, we report a novel mechanistic design to realize efficient ROS catalysis in Yb/Er/CeOF@SiO2@Au upconversion nanoparticles (UCNPs), which protects heart cells from oxidative injury via scavenging cellular ROS. The incorporation of Yb3+ and Er3+ ions acts as a catalytic enhancer, endowing the UCNPs with versatile multienzyme mimicry capabilities, such as those of superoxide dismutase and glutathione peroxidase. Moreover, the Yb/Er/CeOF@SiO2@Au nanoparticles exhibit efficient red upconversion emission and high-temperature sensitivities, resulting in excellent fluorescence localization and temperature stability. H2O2 and LPS-induced myocardial damage can be effectively treated with the injection of UCNPs. Yb/Er/CeOF@SiO2@Au improves mitochondrial function and oxidative phosphorylation, which decreases myocardial cell damage and biotoxicity both in vitro and in vivo. Therefore, Yb/Er/CeOF@SiO2@Au represents a novel nanozyme with significant potential in cardiovascular disease therapeutics.