Benefiting from high efficiency and environmental friendliness, Zn–air batteries, fuel cells and electrochemical H₂O₂ production have attracted significant attention in the energy field. However, the oxygen reduction reaction (ORR), which takes place at the cathode and involves a multi-electron transfer process, has become a barrier to the widespread applications of these pollution-free systems. It is urgent to develop efficient catalysts for the ORR. Single-atom catalysts (SACs), particularly M–N–C SACs (M = non-precious metal atom), have emerged as attractive candidates with maximum metal atom utilization, uniform active centers, strong metal–support interaction and well-defined active sites. In this review, recent developments in improving the intrinsic activity of M–N–C SACs were summarized, emphasizing the impact of the surrounding environment on the ORR performance of single-atom sites as determined by experimental investigations and density functional theory (DFT) simulations. In addition, advanced characterization techniques, synthesis strategies and the applications of M–N–C SACs in Zn–air batteries, proton exchange membrane fuel cells (PEMFCs) and H₂O₂ production were also documented. This review may stimulate the intensive exploration of highly active M–N–C SACs for practical applications in the near future.