The structure, oxygen non-stoichiometry, defect equilibrium, and thermodynamic properties of perovskite-type Pr0.5Ba0.25Sr0.25MnO3–δ manganite were studied. It was shown that the manganite can be air synthesized in one step at 1450 °C. Though having a disordered arrangement of Pr, Ba, and Sr atoms, the compound crystallizes with a tetragonal structure (S.G. I4/mcm) due to the regular tilts of MnO6 octahedra. The oxygen content in oxide as a function of oxygen partial pressure and temperature was measured by coulometric titration, and the data were used for the modeling of defect equilibrium. The oxygen content measurements show stability of the manganite at 973–1223 K and oxygen pressure decrease down to 10−16–10−12 atm. The equilibration of defects in Pr0.5Ba0.25Sr0.25MnO3-δ involves oxygen exchange with the gaseous ambient, intrinsic electron excitation, and oxygen disordering reactions. According to thermodynamic calculations, oxygen sites available for oxygen exchange are characterized by praseodymium-rich coordination. The disordering caused by the half substitution of barium by strontium leads to a lower energy of chemical bonding of the labile oxygen in Pr0.5Ba0.25Sr0.25MnO3–δ compared to the parent Pr0.5Ba0.5MnO3–δ manganite.