The oxygen evolution reaction (OER) is regarded as a critical component in the water splitting system. Creating vacancies, increasing active surface area, and optimizing electronic structure would improve electrocatalytic performance. Herein, a facile electrochemical reduction method is used to generate sulfur vacancies in nickel iron sulfide (NiFe-S) with a large geometry area of 15 × 16 cm2, which is synthesized using an electrodeposition process assisted with the ion exchange (IOE) method. The X-ray absorption spectroscopies (XAS) are applied for atomic-level structural analysis, verifying that electrochemical desulfurization generates abundant S vacancies. The NiFe-S with abundant sulfur vacancies (NiFe-S-Vs) exhibits a low overpotential (252 mV at 100 mA cm−2), and long stability for 260 h at 500 mA cm−2. More importantly, the NiFe-S-Vs catalyst also delivers a small overpotential (235 mV at 1000 mA cm−2) and high alkaline tolerance (140 h at 500 mA cm−2) in 6 M KOH at 60 °C), implying a potentially significant industrial application prospect. Finally, theory calculation further illustrates the high performance of as-prepared vacancies-rich catalyst.