Exploration of efficient antioxidase-like reactive oxygen nanobiocatalysts (ROBCs) is a major challenge in combating oxidative stress-related diseases. Herein, the molecularly well-defined Ru-porphyrin-networks (Ru-Por-Net)-based ROBCs with ultrafast and reversible redox-centers for catalytic elimination of reactive oxygen species (ROS) are reported. Owing to the large π-conjugated networks, Ru–N coordination structures, and unique electronic and redox properties of atomic Ru sites, the Ru-Por-Net-based ROBCs exhibit exceptional catalytic ROS-scavenging activities. It is considerably more efficient than recently reported state-of-the-art anti-ROS biocatalysts. Notably, a new nucleophilic attack pathway to eliminate H2O2 and produce O2 is proposed via theoretical calculations, and the desorption of the OO* process is identified as the rate-determining step of atomic Ru centers. Cellular studies reveal that the new ROBCs can efficiently secure the survival, adhesion, spreading, and differentiation of the stem cells in high-ROS-level microenvironments. In vivo rat periodontitis treatments further demonstrate their superior anti-ROS therapeutic effects. This study provides significant insights into the crucial functions of Ru–N coordinated porphyrin-networks in catalytic ROS-scavenging and offers a new strategy to engineer high-performance antioxidase-like nanobiocatalysts for stem cell-based therapies and inflammatory diseases.