Developing low‐cost, high‐performance electro‐catalysts is essential for large‐scale application of electrochemical energy devices. In this article, reported are the findings in understanding and controlling oxygen defects in PrBa0.5Sr0.5Co1.5Fe0.5O5+δ (PBSCF) for significantly enhancing the rate of oxygen evolution reaction (OER) are reported. Utilizing surface‐sensitive characterization techniques and first‐principle calculations, it is found that excessive oxygen vacancies promote OH− affiliation and lower the theoretical energy for the formation of O* on the surface, thus greatly facilitating the OER kinetics. On the other hand, however, oxygen vacancies also increase the energy band gap and lower the O 2p band center of PBSCF, which may hinder OER kinetics. Still, careful tuning of these competing effects has resulted in enhanced OER activity for PBSCF with oxygen defects. This work also demonstrates that oxygen defects generated by different techniques have very different characteristics, resulting in different impacts on the activity of electrodes. In particular, PBSCF nanotubes after electrochemical reduction exhibit outstanding OER activity compared with the recently reported perovskite‐based catalysts. Oxygen vacancies in PrBa0.5Sr0.5Co1.5Fe0.5O5+δ (PBSCF) are found to promote OH‐ affiliation and lower the theoretical energy for the formation of O* on the surface. However, oxygen vacancies also increase the energy band gap and lower the O 2p band center of PBSCF. Careful tuning of these competing effects has resulted in enhanced oxygen evolution reaction activity for PBSCF with oxygen defects.