Our global climate is changing and the problem got so serious that the European Commission is calling for a climate-neutral Europe by 2050. To reach such an ambitious and urgent goal, an energy efficient renovation of the existing building stock is needed. Nonetheless, some buildings must be treated with special attention because of their historical value. Thus, it is advisable to evaluate their retrofit with the aid of calibrated hygrothermal simulation models, whose calibration can be complex and time demanding. This work shows the strategy adopted for obtaining a calibrated model for a XVI-century construction located northern Italy, by means of indoor air temperature and relative humidity monitoring, plus CO2 measurements and in situ inspection. This study accounts for the first 9 months of measurements performed on the case study and it adopts HAMBase as a simulation tool because of its ability to combine heat and moisture calculations in monumental buildings with HVAC systems. This paper aims at showing the main problems found in developing and calibrating the simulation model while defining a procedure to overcome them. The major outcome of the study is that the stratification of temperature detected in the main monumental room could be successfully modelled via dividing this space into different zones, vertically, by introducing fictitious interzonal surfaces made of a material with high thermal conductivity and vapour permeability. All in all, the strategy adopted in this work can be used by other researchers and professionals to overcome problems that can be commonly met when modelling similar historic constructions.