Many Li-ion cathode materials transform via two-phase reactions, which can lead to long-term structural damage and limited cyclability. To elucidate the coupling between favorable solid-solution Li intercalation and the underlying cation ordering, we take the high-voltage spinel, LixNi0.5Mn1.5O4 (0 ≤ x ≤ 1), as a case example. Through grand canonical Monte Carlo (MC) simulations based on the ab initio cluster expansion model, we show a striking dependence between the solid-solution phase domain and the Ni−Mn cation ordering. The perfectly ordered LixNi0.5- Mn1.5O4 spinel resists solid solution until very high temperatures, but introducing various degrees of Ni−Mn cation disorder results in a dramatic increase in stability for a single-phase reaction, particularly at high Li contents. This opens up the possibility of designing single-phase reaction materials via targeted cation ordering, and to this end, we show that a uniformly distributed cation high-voltage spinel has access to solid solution throughout the entire Li composition range at room temperature.