Zirconium oxide formed in high-temperature water conditions is highly heterogeneous in nature, with, for instance, the presence of a high density of grain boundaries and nanopores, secondary-phase precipitates, and microchemical segregations. Irradiation exacerbates these heterogeneities with effects such as radiation-induced segregation and precipitate dissolution/amorphization. The transport of species through the oxide is affected by these heterogeneities, resulting in complex transport mechanisms that are still not well understood. In this study, we focused on chemical heterogeneities in the oxide, specifically the oxide/metal (O/M) interface and how alloying elements are redistributed across the interface as it progresses into the substrate. For the first time, in situ atom probe tomography (APT) experiments, in which the APT needle is oxidized prior to analysis, have been performed on unirradiated and 1-dpa proton-irradiated Zr-Nb-Fe model alloys to characterize chemical redistribution as a function of oxidation temperature and time across the O/M interface. Results show that the niobium and iron contents in the oxide are higher than what can be accounted for only with solute capture. This finding suggests that there is a thermodynamic driving force for the niobium and iron solutes to migrate from the metal into the oxide in the unirradiated system. Under irradiation, niobium-rich irradiation-induced nanoclusters form in the metal matrix, and the iron and niobium solutes are more thermodynamically stable relative to the unirradiated system. We found much less niobium and iron in the oxide formed in the irradiated sample, corroborating the finding that the substrate is more thermodynamically stable. This finding has strong implications relative to unirradiated versus irradiated Zr-Nb oxidation kinetics because niobium solute doping in the oxide is known to significantly affect the alloy oxidation rate.