Abstract Perovskite iron oxides are promising oxygen carrying materials due to their effectiveness and the low cost of iron. The effect of Ca2+ doping on oxygen ion diffusion in Sr1-xCaxFeO3-δ (x = 0, 0.125, 0.25, 0.375, 0.5) is investigated by combining density functional theory (DFT) calculations and experimental measurements. The oxygen ion diffusion is determined by two key factors of oxygen vacancy formation and migration. The DFT results show that the oxygen vacancy formation energies greatly decrease as Ca2+ content reaches x = 0.125, then gradually decrease with Ca2+ contents up to 0.375, and finally increase as the Ca content reaches x = 0.5. A combination of experimental thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) results corroborate this trend for Ca2+ contents between 0 and 0.4. The Fe-O bonding dominates the effect of Ca2+ doping on the oxygen vacancy formation. Shortened Fe-O bonds cause the decrease in the formation energy at lower Ca2+ contents, while the lengthened bonds by FeO6 octahedron distortion cause the increase in the formation energy at higher Ca2+ contents. Kinetically, the oxygen migration barrier is lowered upon Ca2+ doping through the increasing lattice spacing for oxygen diffusion. Therefore, an appropriate Ca2+ doping of x = 0.125–0.375 promotes the oxygen ion diffusion in Sr1-xCaxFeO3-δ. Our findings provide the effective Ca2+ doping value for Sr1-xCaxFeO3-δ and a material design clue for the isovalent A-site doping system of oxygen carriers.