Anchoring Ir onto metal-oxide support can effectively address the scarcity and insufficient activity problems of Ir-based acidic water oxidation catalysts by triggering the lattice-oxygen-mediated mechanism (LOM). However, the stability of these catalysts is usually sacrificed due to support overoxidation and reconstruction during the LOM pathway. Here, we propose constructing oxygen diffusion paths at a mixed-metal oxide support (ZrOx and TaOx) interface for a stable LOM. The new synthesized Ir-ZrTaOx catalyst exhibits two orders higher mass activity than IrO2 and retains 1,000-h electrolysis. It demonstrates low degradation (4.7 μV h−1) during the 200-h operation in a proton-exchange membrane (PEM) electrolyzer using only 1/4 Ir loading. Operando spectroscopic evidence combined with theory studies suggests that the oxygen diffusion path at the ZrOx/TaOx interface inhibits the overoxidation and detrimental reconstruction of TaOx. The strategy of stabilizing the LOM will benefit the future design of stable and efficient water oxidation catalysts.