The long-term integrity of the bentonite buffer is of significant interest in the performance assessment (PA) of geological nuclear waste disposal. This study aims at understanding how the initial bentonite chemical composition and other geochemical parameters affect long-term chemical properties within the buffer, which will subsequently affect the transport. Using coupled thermal–hydrological–chemical (THC) models for migration of U(VI) in a generic repository, we performed a global sensitivity analysis (GSA) to identify the influence of each parameter on the temporal evolution of a spatially averaged distribution coefficient for the entire buffer. Such an analysis can be used in a repository-scale PA. In this work, we used the toughreact software to model coupled THC processes in a generic clay repository with bentonite buffer. In this model, U(VI) is released from a canister via schoepite dissolution, which is assumed to occur 1000 yr after closure. U(VI) migrates through the bentonite buffer affected by two-site protolysis nonelectrostatic surface complexation and cation exchange (2 SPNE SC/CE). GSA results showed that adsorption density on smectite, pH, volume fractions of smectite, calcite, and Ca+2 aqueous concentration all play a significant role in U(VI) transport, since roughly 80% of adsorbed U(VI) is absorbed by smectite, and Ca+2 affects the aqueous complexation with U(VI). This work demonstrates the complex process models' potential usefulness that can be transferred to the PA model. It also provides information needed to proceed with the development of a reduced-order model, which has the potential to optimize repository designs, site characterization, and performance confirmation.