Update information. Effective therapeutic strategies for myocardial ischemia/reperfusion (I/R) injury are still lacking. Targeting reactive oxygen species (ROS), the major cause of I/R injury, provides a practical approach to alleviate myocardial damage after reperfusion procedure. Herein, we synthesized an innovative antioxidant nanozyme equipped with single-platinum-atom (PtsaN-C) for protecting against I/R injury. PtsaN-C exhibited potent multiple enzyme-mimicking activities with high-efficiency ROS-scavenging. Mechanistic studies demonstrated that excellent ROS-elimination performance in single platinum atom center was prior to that of platinum cluster center attributing to good synergistic effect and metallic electronic property with nitrogen-doping coordination structure. Systematic in vitro and in vivo studies confirmed that PtsaN-C counteracted ROS efficiently to restore cellular homeostasis and prevented apoptotic progress after I/R injury. PtsaN-C presented excellent biocompatibility and biosafety, making it promising for future clinical application. Current study broadens the horizon of single-atom nanomedicine against ROS-induced damage, offering a promising therapeutic avenue for treatment of I/R injury.