The electro-oxidation of water to oxygen is expected to play a major role in the development of future electrochemical energy conversion and storage technologies. However, the slow rate of the oxygen evolution reaction remains a key challenge that requires fundamental understanding to facilitate the design of more active and stable electrocatalysts. Here, we probe the local geometric ligand environment and electronic metal states of oxygen-coordinated iridium centres in nickel-leached IrNi@IrOx metal oxide core–shell nanoparticles under catalytic oxygen evolution conditions using operando X-ray absorption spectroscopy, resonant high-energy X-ray diffraction and differential atomic pair correlation analysis. Nickel leaching during catalyst activation generates lattice vacancies, which in turn produce uniquely shortened Ir–O metal ligand bonds and an unusually large number of d-band holes in the iridium oxide shell. Density functional theory calculations show that this increase in the formal iridium oxidation state drives the formation of holes on the oxygen ligands in direct proximity to lattice vacancies. We argue that their electrophilic character renders these oxygen ligands susceptible to nucleophilic acid–base-type O–O bond formation at reduced kinetic barriers, resulting in strongly enhanced reactivities.