It is widely accepted that solid oxide fuel cells (SOFCs) have the potential to be the most efficient and cost-effective system for the direct conversion of various fuels into electricity with low environmental pollution and high efficiency. Herein, we demonstrate a novel Fe-based high-entropy perovskite oxide as a cathode material for intermediate-temperature solid oxide fuel cells (IT-SOFCs). The high-entropy perovskite La0.2Pr0.2Sm0.2Nd0.2Sr0.2FeO3-δ (HE-LSF), composed of La, Pr, Nd, Sm, and Sr is prepared by incorporating five components into the A-site of La0.8Sr0.2FeO3-δ (LSF). Doping of Pr, Nd, Sm, and Sr into the A-site significantly enhances the redox stability of LSF and restrains the surface Sr-segregation in both oxidizing and reducing conditions. The electrode polarization resistance of the anode-supported single cell with HE-LSF cathode is significantly low at intermediate temperature. Meanwhile, at 800 °C, the power density is 1029.2 mW/cm2, and the polarization resistance (Rp) is 0.101 Ω cm2, while at 700 °C, the power density is 581.52 mW/cm2 with an Rp of 0.21 Ω cm2 in humidified H2. Further, the HE-LSF cathode presents good and long-term stability at a constant voltage of 0.7 V for 100 h at 700 °C. The excellent electrochemical performance and stability results exhibit that Fe-based high-entropy perovskite oxide is a new promising candidate and cathode material for SOFCs at intermediate temperatures.