Manganese-based mullite (AMn2O5) catalysts are promising for the catalytic oxidation of VOCs, with their oxidation reaction performance being tunable by modifying the composition of the A-site elements. In this work, various manganese-based mullite catalysts (Gd0.9X0.1Mn2O5, X =Sr, Ce, or Ca) with different A-site elements doping were prepared by the citric acid sol–gel method and applied to the catalytic oxidation of toluene. The activity tests indicated that the enhancement of catalytic performance by doping elements was in the order of Sr > Ce > Ca. Notably, the T90 of the Gd0.9Sr0.1Mn2O5 catalyst was 235.6 °C, a lower 37.8 °C than that of the GdMn2O5. Comprehensive characterization and density functional theory (DFT) simulations revealed that Sr doping facilitates the reduction of Mn4+ to Mn3+, increases the electron occupancy of the eg orbitals in octahedral Mn sites, and elevates the Mn-d band center, thus facilitating the adsorption and activation of O2. Additionally, the raised O-p band center caused by Sr doping enhances lattice oxygen mobility. In situ DRIFTS analysis indicated that the introduction of Sr at the A-site optimizes the toluene reaction pathway and accelerates the reaction rate. This work reveals that a simple A-site cation doping strategy can effectively regulate manganese-based mullite catalysts’ electronic structure and surface reaction activity, providing a feasible method for the large-scale preparation of manganese-based mullite catalysts with excellent catalytic performance.