The long-term thermal-hydraulic-mechanical response of a generic salt repository for high-level nuclear waste is investigated. In-drift emplacement of the waste packages and subsequent backfill of the drifts with crushed salt are assumed. The aim of this research is to evaluate the long-term integrity of the natural salt and consolidated backfill barriers. For this purpose, we use an updated version of the TOUGH-FLAC simulator, able to deal with large strains and creep. The simulator also includes state-of-the-art constitutive relationships and coupling functions. The Lux/Wolters constitutive model for natural salt is used. The simulations are two-way coupled and include the stages of excavation, waste emplacement, backfilling and a post-closure period of 100,000 years. The simulation results show that the excavation damaged zone is healed within the first years and that the backfill reconsolidation is complete within the first decades. Depending on the magnitude of the pore pressure relative to the minimum principal stress, hydraulic damage within the host rock may occur at a larger scale. The comparison of coupled simulation results with those issued from a case that disregards the mechanical processes shows the necessity to account for the mechanical effect in order to accurately predict the long-term evolution of the barriers.