Mayenite (Ca₁₂Al₁₄O₃₃, C₁₂A₇), and its electride variant (C₁₂A₇:2e^–) have attracted attention as functional materials with high ionic conductivity, and for potential uses in oxidation catalysis, fuel cells, and hydrogen storage. In contrast to anionic substitutions into C₁₂A₇, less is known about the influence of cationic substitutions on this material. This study applies DFT methods to rigorously understand the influences of Mg²⁺, Cu²⁺, Sr²⁺, Fe³⁺, Ir⁴⁺, P⁵⁺ and V⁵⁺ (2+ ≤ Z_V ≤ 5+, where Z_V is the cation valence, unitless) substitutions on the structural and electronic features of C₁₂A₇ and its electride variant. Substitutions alter the lattice parameters, in relation to their size, and alter charge localization. Substitutions also affect mayenite’s cage framework, resulting in the formation of a “window” that connects two adjacent cages. While Mg²⁺, Sr²⁺, P⁵⁺, and V⁵⁺substitutions maintain their F⁺-like attractive nature, Cu²⁺, Fe³⁺, and Ir⁴⁺ neutralize such a tendency in the cages of their corresponding C₁₂A₇ electride. Therefore, the conduction mechanism of mayenite electride (i.e., containing Cu²⁺, Fe³⁺, and Ir⁴⁺) switches from e^–-hopping to band conduction electrons. The insertion of Cu²⁺-substitutions makes the window between two adjacent nanocages collapse, resulting in the formation of a transport channel between two neighboring [Ca–Al–O] cages for localized electrons. The outcomes suggest novel means to induce electron coupling between nearest-neighbor cages in mayenite, an aspect of interest for tailoring the electron transport properties of mayenite and other light-metal oxide electrides.