This study presents a microscopic model for the correlation between the concentration of oxygen vacancies and voltage suppression in high voltage spinel cathodes for Li-ion batteries. Using first principles simulations, it is shown that neutral oxygen vacancies in LiNi0.5Mn1.5O4-δ promote substitutional Ni/Mn disorder and the formation of Ni-rich and Ni-poor regions. The former trap oxygen vacancies, while the latter trap electrons associated with these vacancies. This leads to the creation of deep and shallow Mn3+ states and affects the stability of the lattice Li ions. Together, these two factors result in a characteristic profile of the voltage dependence on Li content. This insight provides guidance for mitigating the voltage suppression in LiNi0.5Mn1.5O4 and other cathodes.