High levels of humidity in buildings lead to building pathologies. Moisture also has an impact on the indoor air quality and the hygrothermal comfort of the building’s occupants. To better assess these pathologies, it is necessary to take into account the heat and moisture transfer between the building envelope and its indoor ambience. In this work, a new methodology was developed to predict the overall behavior of buildings, which combines two simulation tools: COMSOL Multiphysics^© and TRNSYS. The first software is used for the modeling of heat, air and moisture transfer in multilayer porous walls (HAM model: Heat, Air and Moisture transfer), and the second is used to simulate the hygrothermal behavior of the building (BES model: Building Energy Simulation). The combined software applications dynamically solve the mass and energy conservation equations of the two physical models. The HAM-BES coupling efficiency was verified. In this paper, the use of a coupled (HAM-BES) co-simulation for the prediction of the hygrothermal behavior of building envelopes is discussed. Furthermore, the effect of the 2D HAM modeling on relative humidity variations within the building ambience is shown. The results confirm the importance of the HAM modeling in the envelope on the hygrothermal behavior and energy demand of buildings.