Sodium-ion batteries have the potential to meet the growing demand for energy storage due to their low costs stemming from natural resource abundances, but their cathode energy densities must be improved to be comparable to those of lithium-ion batteries. One strategy is accessing high voltage capacity through high-valent redox reactions. Such reactions usually cause instability in cathode materials, but Na2Mn3O7 (NMO) has demonstrated excellent performance and reversibility in the high-valent regime due to its unique lattice structure with ordered Mn vacancies. This work expands the universality of the ordered vacancy as a design principle and increases the material candidates with such exceptional electrochemical behavior. Our approach involves synergizing cationic ordered vacancies with tunable metal-ligand hybridization through partial metal substitution. In particular, we successfully incorporated Fe3+ for Mn4+ in NMO to make Na2.25Mn2.75Fe0.25O7 and achieved improved high-valent redox behavior. Fe substitution leads to larger specific capacities (171 vs. 159 mA h g−1 first cycle), enhanced cycle stability (97 vs. 60 mA h g−1 after 50 cycles), and superior rate performance. This study lays the foundation for developing new cathode materials with stable high-valent redox through substitution of redox-active transition metals by employing cationic ordered vacancies and partial transition metal substitution as design principles in tandem.