AbstractThe development of highly active and durable platinum‐free oxygen reduction reaction (ORR) catalysts is of vital importance for the practical application of anion‐exchange membrane fuel cells (AEMFCs). Herein, a metal‐free carbon catalyst (marked as NDPC‐1000) with a graphitic N‐regulating defect structure is specifically designed and developed for AEMFCs by integrating theoretical calculations and experiments. Density functional theory calculations first reveal that the graphitic N can tailor the charge density of pentagon and armchair defects to reach the top of the adsorption energy‐activity volcano plot, while the enhanced durability is attributed to the high dissociation energy of the CN covalent bond. Under this guidance, the synthesized NDPC‐1000 demonstrates its high ORR activity and durability in alkaline media. With H₂/O₂ reacting gases, the AEMFC with this catalyst as the cathode delivers a peak power density of 913 mW cm⁻². Unprecedented fuel cell durability is verified via continuous operation over 100 h at 0.25 A cm⁻² with only a voltage decay of ≈25%, which is the greatest among all reported metal‐free‐based AEMFCs. Here a theory‐guided experiment strategy is provided for the development of high‐performance and durable ORR catalysts for AEMFCs.