The aim of our present study was to assess and compare the thermo-physical and energy behaviour of different integrated building façades, using a multi-physics simulation approach. Advanced integrated façades composed of opaque modules, one of them with a phase change materials (PCM) layer, the others with multilayer panels, combined with transparent ones, consisting of nano-structured materials and new-generation photovoltaic systems, were investigated. A multi-physics approach was used for the design optimization of the studied components and evaluation of their thermo-physical and heat transfer performance. In particular, computational fluid dynamics (CFD) multi-physics transient simulations were performed to assess air temperature and velocity fields inside the ventilated cavities. Analysis of heat and mass exchange through all the components was assessed during heating and cooling mode of a reference building. The typical Mediterranean climate was considered. Results comparison allowed the dynamic heat transfer evaluation of the multilayer façades as a function of variable climatic conditions, and their flexibility and adaptability exploitation, when different energy strategies are pursued. The multi-physics modelling approach used, proved to be a strong tool for the energy design optimization and energy sustainability evaluation of different advance materials and building components.