Transition metal single atom catalysts (TM SACs) are the most promising oxygen reduction reaction (ORR) catalysts for proton exchange membrane fuel cells (PEMFCs) and metal-air batteries. However, the low density of M-Nx active sites seriously hinders further improvement of the ORR electrocatalytic activity. Here, a strategy for encapsulating nitrogen-rich guest molecules (triethylenediamine cobalt complex, [Co(en)3]3+) was proposed to construct a high-performance cobalt single-atom catalyst (Co-encapsulated SAC/NC). With this strategy, the guest molecules are encapsulated into metal–organic framework (MOF) cages as an additional cobalt source to boost cobalt loading, while abundant nitrogen from guest molecules contributes to the formation of Co-N4 active sites. Remarkably, the resulting Co-encapsulated SAC/NC has a high cobalt loading amount of 4.03 wt%, and spherical aberration-corrected transmission electron microscopy (AC-TEM) has confirmed that most cobalt exists in a single-atom state. As a result, the Co-encapsulated SAC/NC exhibits excellent ORR catalytic performance with a half-wave potential of 0.88 V. Furthermore, Zn-air batteries employing Co-encapsulated SAC/NC as air cathode show high peak power density and excellent cycling stability. Density functional theory (DFT) calculations reveal that adjacent active sites have different rate-determining steps and lower reaction energy barriers than a single active site.