Nickel‐based oxide catalysts are widely used for the oxygen evolution reaction (OER) in alkaline water electrolysis because of their low cost and high activity. In particular, the LiNiO2 catalyst shows high activity. Therefore, to elucidate the fundamental relationship between the local structure, catalyst activity, and stability of LiNiO2, we investigated the cation mixing effect by mixing sites of lithium and nickel ions in the LiNiO2‐based catalysts. Lower degrees of cation mixing lead to higher intrinsic OER activity but lower long‐term stability. The X‐ray absorption spectra (XAS) displayed a strong hybridization state of the Ni 3d and O 2p orbitals, which is the origin of the different catalytic activity behaviors. Meanwhile, operando XAS studies combined with potentiostatic stability tests and inductively coupled plasma optical emission spectrometry (ICP‐OES) demonstrated the Li ion loss during the OER process. Thus, the instability of LiNiO2 originates from de‐intercalation of Li ions and this irreversible structure change deteriorates the performance. Hindering the lithium diffusion path by cation mixing is a useful strategy for maintaining performance. This strategy could provide a novel design principle for compatible high activity and long‐lasting catalysts by reasonable structure mediation.