The oxygen evolution reaction (OER) constitutes the key limiting process in water electrolysis, and various catalysts have recently been introduced to improve OER efficiency. Vacancy engineering in the crystal lattice is particularly promising in catalyst design, as vacancies could perturb the electronic properties of adjacent atoms to make them catalytically active. Noting that one of the well-adopted approaches to induce vacancies in a crystal structure is the mixing of elements with different valence states, herein, we investigate crystalline NiFe-V-M-O in comparison with NiO. Vacancies are naturally generated to meet charge neutrality when Ni2+ and Fe3+ are mixed via solid solution. As a result of vacancy formation, NiFe-V-M-O exhibits markedly enhanced catalytic performance for the OER. A combined in situ X-ray absorption fine structure and density functional theory analysis reveals that transition metal vacancies in NiFe-V-M-O distort the adjacent Ni's electronic structure toward weakening the interaction with the reaction intermediate *O, which is also associated with the enhanced structural flexibility of NiFe-V-M-O involving the transition metal vacancies. This study demonstrates the usefulness of the "vacancy-local structure-electronic property" relationship as a tool in manipulating the catalytic properties of OER electrocatalysts.