Demonstrated here is the correlation between atomic configuration induced electronic density of single‐atom Co active sites and oxygen reduction reaction (ORR) performance by combining density‐functional theory (DFT) calculations and electrochemical analysis. Guided by DFT calculations, a MOF‐derived Co single‐atom catalyst with the optimal Co1‐N3PS active moiety incorporated in a hollow carbon polyhedron (Co1‐N3PS/HC) was designed and synthesized. Co1‐N3PS/HC exhibits outstanding alkaline ORR activity with a half‐wave potential of 0.920 V and superior ORR kinetics with record‐level kinetic current density and an ultralow Tafel slope of 31 mV dec−1, exceeding that of Pt/C and almost all non‐precious ORR electrocatalysts. In acidic media the ORR kinetics of Co1‐N3PS/HC still surpasses that of Pt/C. This work offers atomic‐level insight into the relationship between electronic density of the active site and catalytic properties, promoting rational design of efficient catalysts. The correlation between atomic configuration induced electronic density of single‐atom Co active sites and oxygen reduction reaction (ORR) performance has been established by combining density‐functional theory calculations and electrochemical analysis. A metal–organic framework derived single‐atom Co catalyst, comprising an optimal Co1‐N3PS active moiety supported on hollow carbon polyhedron (Co1‐N3PS/HC), was synthesized, and it exhibits superior alkaline and acidic ORR performance.