This paper investigates the transient hygrothermal performance of an innovative energy and seismic renovation solution for reinforced concrete (RC) framed buildings, based on the addition of Cross-Laminated Timber (CLT) panels to the outer walls, in combination with wood-based insulation. This solution is being developed in the framework of a four-year EU-funded project called e-SAFE. The investigation relies on numerical simulations in DELPHIN 6.1, by considering combined heat and mass transfer (HAMT) due to water vapour diffusion and capillary transport. The proposed solution is tested in three different climates in Italy, to verify whether the CLT layer and the outer waterproof vapour-open membrane, inserted to protect the wood-based insulation from rain, still allow the effective drying of the vapour accumulated in liquid form in the walls, while also preventing mould formation. The results show that the increased thermal resistance of the wall assembly significantly reduces the total water content, although moderate risks of mould growth in the wooden materials may occur in coldest climates.