Nb-doped SrFeO 3−δ (SFO) is used as a cathode in proton-conducting solid oxide fuel cells (H-SOFCs). Firstprinciples calculations show that the SrFe 0.9 Nb 0.1 O 3−δ (SFNO) cathode has a lower energy barrier in the cathode reaction for H-SOFCs than the Nb-free SrFeO 3−δ cathode. Subsequent experimental studies show that Nb doping substantially enhances the performance of the SrFeO 3−δ cathode. Then, oxygen vacancies (V O ) were introduced into SFNO using the microwave sintering method, further improving the performance of the SFNO cathode. The mechanism behind the performance improvement owing to V O was revealed using first-principles calculations, with further optimization of the SFNO cathode achieved by developing a suitable wet chemical synthesis route to prepare nanosized SFNO materials. This method significantly reduces the grain size of SFNO compared with the conventional solid-state reaction method, although the solid-state reaction method is generally used for preparing Nb-containing oxides. As a result of defect engineering and synthesis approaches, the SFNO cathode achieved an attractive fuel cell performance, attaining an output of 1764 mW•cm −2 at 700 °C and operating for more than 200 h. The manipulation of Nb-doped SrFeO 3−δ can be seen as a "one stone, two birds" strategy, enhancing cathode performance while retaining good stability, thus providing an interesting approach for constructing high-performance cathodes for H-SOFCs.