Since January 2020 Italy has been countering the COVID-19 pandemic with several measures, including strategies to improve the National Health System’s preparedness to such a threat. The paper aims to analyse response plans and measures against the COVID-19 pandemic within the Italian healthcare system, at national and regional level. Two objectives have been set: reviewing governmental provisions for territorial and hospital health services rearrangement; reviewing operational responses on the regional scale to address those demands. To collect and review operational responses at the regional level, six Regions have been considered as the field of study, chosen for being a relevant sample of the resident population in North, Middle and South Italy. Comparative analyses have been carried out to outline similarities and differences in managing this difficult healthcare situation. Results show that territorial medicine, particularly epidemiologic service, has been essential in facing the national crisis, but hospitals have been the main actors in addressing COVID-19 needs. Relevant structural, technological and organisational changes were needed to prepare hospitals. The built environment plays a significant role in managing the pandemic response, indeed. Further efforts to develop a novel, resilient and sustainable hospital model are needed. This study contributes to a better understanding of factors influencing current Italian hospitals’ strengths and limitations, shedding light on future design models which can increase resilience in emergency conditions.