Electrochemical oxygen reduction reaction (ORR) via the 2e− pathway in an acidic media shows great techno-economic potential for the production of hydrogen peroxide. Currently, carbon-based single-atom catalysts (C-SACs) have attracted extensive attention due to their tunable electronic structures, low cost, and sufficient stability in acidic media. This review summarizes recent advances in metal centers and their coordination environment in C-SACs for 2e−-ORR. Firstly, the reaction mechanism of 2e−-ORR on the active sites of C-SACs is systematically presented. Secondly, the structural regulation strategies for the active sites of 2e−-ORR are further summarized, including the metal active center, its species and configurations of nitrogen coordination or heteroatom coordination, and their near functional groups or substitute groups, which would provide available and proper ideas for developing superior acidic 2e−-ORR electrocatalysts of C-SACs. Finally, we propose the current challenges and future opportunities regarding the acidic 2e−-ORR pathway on C-SACs, which will eventually accelerate the development of the distributed H2O2 electrosynthesis process.