Dual alkaline earth-substituted Pr0.94Ba1–2xSrxCaxCo2O5+δ perovskites are evaluated as potential cathodes for intermediate-temperature solid oxide fuel cells. When incorporating Sr2+ and Ca2+ into the lattice, the phase transformation from tetragonal layered perovskite to simple cubic perovskite can be identified. Benefitting from enhanced electrical conductivity, oxygen surface exchange and ionic diffusion rates, the as-prepared perovskite catalysts demonstrate highly electrocatalytic activity for oxygen reduction reaction. The Pr0.94Ba0.6Sr0.2Ca0.2Co2O5+δ cathode exhibits an area-specific resistance of 0.025 Ω cm2 at 700 °C, approximately decreased by = 60% relative to the pristine Pr0.94BaCo2O5+δ. It is discovered that Sr2+ and Ca2+ co-substituting lowers the charge transfer energy, as well as oxygen adsorption energy. Furthermore, the Pr0.94Ba0.6Sr0.2Ca0.2Co2O5+δ cathode-based fuel cell delivers a peak power density of 1194 mW cm−2 at 700 °C, along with outstanding short-term stability over a period of 160 h. Our results highlight a strategy of dual alkaline earth substitution for rationally designing the perovskite electrocatalysts.