The oxygen content in La_0.5Sr_0.5Fe_1−xMn_xO_3−δ, measured by coulometric titration in a wide range of oxygen partial pressure at various temperatures, was used for defect chemistry analysis. The obtained data were well approximated by a model assuming defect formation in La_0.5Sr_0.5Fe_1−xMn_xO_3−δvia Fe³⁺ and Mn³⁺ oxidation reactions and charge disproportionation on Fe³⁺ and Mn³⁺ ions. The partial molar enthalpy and entropy of oxygen in La_0.5Sr_0.5Fe_1−xMn_xO_3−δ obtained by statistical thermodynamic calculations were found to be in satisfactory agreement with those obtained using the Gibbs–Helmholtz equations, thus further confirming the adequacy of the model. The impact of manganese substitution on defect equilibrium in La_0.5Sr_0.5Fe_1−xMn_xO_3−δ was shown to be attributed to a lower enthalpy of Mn³⁺ oxidation reaction (vs. for the oxidation of Fe³⁺) and the charge disproportionation reaction on Mn³⁺ (vs. for that on Fe³⁺). The former makes Mn⁴⁺ ions more resistant to reduction than Fe⁴⁺. The latter favors the presence of Mn²⁺, Mn³⁺, and Mn⁴⁺ ions in oxides in comparable concentrations. The distribution of charge carriers over iron and manganese ions was determined as a function of oxygen content in La_0.5Sr_0.5Fe_1−xMn_xO_3−δ.