Microclimate change related events affect cities total environment and therefore citizens’ wellbeing. In a framework of urban resilience challenge, it is important to guarantee thermally comfortable conditions to dwellers in outdoors but also to preserve cultural heritage masterpieces for tourism and local socio-cultural identity. This work couples an innovative field monitoring at multiple scales and a validated numerical modelling effort to identify indoor and outdoor critical conditions at the present time and in the future, according to IPCC climate change forecast scenarios. The authors focused the attention on the overheating risk of Gubbio historical city center, in central Italy. Experimental data analysis highlights the microclimate granularity of the case study with detected temperature discrepancies up to 2.5 °C observed at pedestrian height during the hottest hour, i.e. 2p.m. Collected data are then used to validate the numerical models of (i) the most significant building of the city and (ii) its surroundings to investigate indoor/outdoor thermal comfort stress due to climate change and local overheating. The combined analysis shows that indoor operative temperature reaches 32 °C on average in 80 years, compared to the current 29 °C value. In the outdoors, apparent temperature increases by about 10 °C on 2100, being responsible for a serious threat compromising socio-cultural life, human health and outdoor and recreational activities.