U cations were immobilized in the traditional Sr2Fe2O6-δ (SFO) oxide, which was subsequently evaluated as a cathode for proton-conducting solid oxide fuel cells (H–SOFCs). Experimental studies indicated that the U cations could be incorporated into the SFO lattice, forming the new Sr2Fe1.5U0.5O6-δ (SFUO) oxide material. The SFUO material exhibited improved chemical stability than the SFO material, preventing the formation of carbonates after treatment in a CO2 atmosphere. Although the total electrical conductivity was decreased with the U-doping, the surface catalytic activity of SFUO was improved compared with SFO, which was demonstrated by first-principles calculations. The subsequent electrochemical studies indicated that an H–SOFC using the SFUO cathode showed higher fuel cell output and smaller polarization resistance than the SFO cathode. The present study demonstrated that SFO could locate U cations in the lattice, and the produced SFUO oxide exhibited improved performance, suggesting the utilization of SFO cathode in the harsh environment (such as U-containing conditions) would be possible, and the electrochemical performance of the fuel cell is not reduced.