A novel in situ replication and polymerization strategy is developed for the synthesis of Fe-N-doped mesoporous carbon microspheres (Fe-NMCSs). This material benefits from the synergy between the high catalytic activity of Fe-N-C and the fast mass transport of the mesoporous microsphere structure. Compared to commercial Pt/C catalysts, the Fe-NMCSs show a much better electrocatalytic performance in terms of higher catalytic activity, selectivity, and durability for the oxygen reduction reaction.