Pr(Ba,Sr)Co2O5+δ is a promising cathode material for solid oxide fuel cell (SOFC) due to its high oxygen ion transport capability and oxygen reduction activity. Density functional theory (DFT) calculations were performed to elucidate the oxygen reduction mechanism of B-site doped Pr(Ba,Sr)(Co,M)2O5+δ (M = Fe, Ni, Cu, and Zn) materials. First, we investigated the formation of O vacancies. The results indicate that Cu and Zn doping facilitate O vacancy formation, resulting in lower O vacancy formation energies. Furthermore, the interaction between oxygen and the (0 0 1) surfaces of B-site doped Pr(Ba,Sr)(Co,M)2O5+δ has been comprehensively discussed, involving both perfect and defective surfaces. The results demonstrate that the presence of O vacancies enhances the catalytic activity for oxygen reduction, by reducing the energy required for O2 dissociation. Zn-doped Pr(Ba,Sr)(Co,M)2O5+δ exhibits a low O vacancy formation energy, resulting in a stable adsorption configuration upon oxygen dissociation, indicating its potential as a cathode material for SOFC.