AbstractEnzyme‐mimicking nanomaterials for antioxidative therapy is a promising star to treat more than 200 diseases or control their progressions through scavenging excessive reactive oxygen species (ROS), such as O₂^•− and H₂O₂. However, they can inversely produce stronger ROS (e.g., •OH) under many disease conditions (e.g., low pH for myocardial ischemia). Herein, a biocompatible ‐Cu‐O‐Zn‐ bimetallic covalent doped carbon dots (CuZn‐CDs) processing both catalase (CAT) and superoxide dismutase activities are reported, mainly because of their abundant electrons and the excellent electron transfer abilities. In addition, Cu dopant helps to balance the positive charge at Zn dopant resulting from low pH, enabling CuZn‐CDs to still process CAT ability rather than peroxidase ability. Benefiting from it, CuZn‐CDs exhibit sufficient in vitro ROS scavenging ability and cardiomyocyte protective effect against ROS‐induced damage. In vivo results further demonstrate that CuZn‐CDs can protect the heart from ischemia‐reperfusion injury. In addition to antioxidative therapy, the rapid renal clearance and low toxicity properties of CuZn‐CDs in animal model reveal high biocompatibility which will facilitate clinical use.