Future renewable energy supply and a cleaner Earth greatly depend on various crucial catalytic reactions for the society. Atomically dispersed metal site electrocatalysts (ADMSEs) have attracted tremendous research interest and are considered as the next-generation promising oxygen reduction reaction (ORR) electrocatalysts due to the maximum atom utilization efficiency, tailorable catalytic sites, and tunable electronic structures. Despite great efforts have been devoted to the development of ADMSEs, the systematic summary for design principles of high-efficiency ADMSEs is not sufficiently highlighted for ORR. In this review, the authors first summarize the fundamental ORR mechanisms for ADMSEs, and further discuss the intrinsic catalytic mechanism from the perspective of theoretical calculation. Then, the advanced characterization techniques to identify the active sites and effective synthesis methods to prepare catalysts for ADMSEs are also showcased. Subsequently, a special emphasis is placed on effective strategies for the rational design of the advanced ADMSEs. Finally, the present challenges to be addressed in practical application and future research directions are also proposed to overcome the relevant obstacles for developing high-efficiency ORR electrocatalysts. This review aims to provide a deeper understanding for catalytic mechanisms and valuable design principles to obtain the advanced ADMSEs for sustainable energy conversion and storage techniques.