Searching for a renewable energy system is always the goal to fulfill sustainable development for the future. Water oxidation is considered as a crucial reaction to attain sustainable energy systems. Inspired by the biological Mn₄CaO₅ cluster, considerable effort has been devoted to developing highly efficient Mn-based heterogeneous catalysts and exploring intrinsic mechanism for water oxidation. This review begins with describing the structural characteristics of the Mn₄CaO₅ cluster and the proposed catalytic cycle. Then, the structural characteristics of synthetic Mn-based heterogeneous catalyst are summarized, with emphasis on the understanding of reaction mechanisms and the rate-determining steps. Finally, the strategy of understanding the catalytic mechanism of Mn-based water oxidation is prospected.