Single-atom catalysts (SACs) are considered as the most promising nonprecious metal alternatives for oxygen reduction reactions (ORR) in proton exchange membrane fuel cells because of their high atomic utilization and excellent catalytic performance. However, the inadequate activity and long-term stability of SACs under operational conditions significantly hinder their practical application. Therefore, this paper focuses on understanding the micro- and electronic structures that synergistically enable the activity and stability of oxygen reduction. It provides a comprehensive summary of the effects for improving the ORR catalytic activity and stability of SACs from a multilevel, multi-angle perspective, including macroscale adjustments to the overall catalyst structure, nanoscale optimization of the catalyst microstructure, and atomic-scale regulation of the active sites. Additionally, it emphasizes the importance of advanced simulation, computational methods, and characterization techniques in understanding the catalytic and degradation mechanisms of SACs during the ORR process. This review aims to provide a theoretical foundation for the synergistic catalytic mechanisms and long-term stable operation of catalytic sites in complex heterogeneous environments, thereby advancing research on low-cost, high-efficiency, and highly stable single-atom catalysts.