The development of reliable and safe high‐energy‐density lithium‐ion batteries is hindered by the structural instability of cathode materials during cycling, arising as a result of detrimental phase transformations occurring at high operating voltages alongside the loss of active materials induced by transition metal dissolution. Originating from the fundamental structure/function relation of battery materials, the authors purposefully perform crystallographic‐site‐specific structural engineering on electrode material structure, using the high‐voltage LiNi0.5Mn1.5O4 (LNMO) cathode as a representative, which directly addresses the root source of structural instability of the Fd3¯m structure. By employing Sb as a dopant to modify the specific issue‐involved 16c and 16d sites simultaneously, the authors successfully transform the detrimental two‐phase reaction occurring at high‐voltage into a preferential solid‐solution reaction and significantly suppress the loss of Mn from the LNMO structure. The modified LNMO material delivers an impressive 99% of its theoretical specific capacity at 1 C, and maintains 87.6% and 72.4% of initial capacity after 1500 and 3000 cycles, respectively. The issue‐tracing site‐specific structural tailoring demonstrated for this material will facilitate the rapid development of high‐energy‐density materials for lithium‐ion batteries. Crystallographic‐site‐specific structural engineering is performed on the cathode material structure for lithium‐ion batteries, aiming at the root causes of the instability based on the fundamental structure/function relationship. The high‐voltage spinel LiNi0.5Mn1.5O4 (LNMO) cathode with Fd3¯m space group symmetry is employed as a representative, of which two issue‐involved crystallographic sites are directly and simultaneously addressed, contributing to an extraordinarily excellent battery performance.