The Nb-doped SrFeO_3-δ material is used as a cathode in proton-conducting solid oxide fuel cells (H-SOFCs). First-principles calculations show that the SrFe_0.9Nb_0.1O_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 traditional 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. 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.