The garnet structure is a promising nuclear waste form because it can accommodate various actinide elements. Yttrium iron garnet, Y3Fe5O12 (YIG), is a model composition for such substitutions. Since cerium (Ce) can be considered an analogue of actinide elements such as thorium (Th), plutonium (Pu), and uranium (U), studying the local structure and thermodynamic stability of Ce-substituted YIG (Ce:YIG) can provide insights into the structural and energetic aspects of large ion substitution in garnets. Single phases of YIG with Ce substitution up to 20 mol % (Y3–xCexFe5O12 with 0 ≤ x ≤ 0.2) were synthesized through a citrate–nitrate combustion method. The oxidation state of Ce was examined by X-ray absorption near edge structure spectroscopy (XANES); the oxidation state and site occupancy of iron (Fe) as a function of Ce loading also was monitored by 57Fe–Mössbauer spectroscopy. These measurements establish that Ce is predominantly in the trivalent state at low substitution levels, while a mixture of trivalent and tetravalent states is observed at higher concentrations. Fe was predominately trivalent and exists in multiple environments. High temperature oxide melt solution calorimetry was used to determine the enthalpy of formation of these Ce-substituted YIGs. The thermodynamic analysis demonstrated that, although there is an entropic driving force for the substitution of Ce for Y, the substitution reaction is enthalpically unfavorable. The experimental results are complemented by electronic structure calculations performed within the framework of density functional theory (DFT) with Hubbard-U corrections, which reproduce the observed increase in the tendency for tetravalent Ce to be present with a higher loading of Ce. The DFT+U results suggest that the energetics underlying the formation of tetravalent Ce involve a competition between an unfavorable energy to oxidize Ce and reduce Fe and a favorable contribution due to strain-energy reduction. The structural and thermodynamic findings suggest a strategy to design thermodynamically favorable substitutions of actinides in the garnet system.