Due to COVID-19, telemedicine solutions, in general, have played a crucial role, with their ability to minimize physical physician-patient contacts, and to optimize healthcare system capacity, during demand surges, guaranteeing the taking in charge of the patients and the continuity of care. The present study aims at investigating the feasibility and economic/organizational sustainability of an innovative telemedicine platform, as an example of telemonitoring care programs for patients with or without COVID-19, integrated with telerehabilitation and tele-supporting activities (whose name is T-CUBE), by addressing the following research questions: i) Which are the main benefits related to T-CUBE introduction in the clinical practice, from a clinical and an economic perspectives?; ii) Which are the key factors determining the intention to use T-CUBE in the clinical practice? A Health Technology Assessment (HTA) was conducted in the year 2020, thus examining all the dimensions proposed by the Model for Assessment of Telemedicine (MAST), thus comparing T-CUBE implementation, with the usual care consisting of on-site monitoring and rehabilitative activities. The HTA was then integrated with an in-depth analysis of all the factors that could predict T-CUBE individual’s acceptance, focusing on social and cognitive instrumental factors, and based on the Technology Acceptance Model framework. Literature declared that telemonitoring and tele-supporting would improve the management of patients’ with or without COVID-19, optimizing the care by detecting clinical deterioration at an early stage, caused both by COVID-19 or chronic cardiac or pulmonary diseases, thus also revealing a lower hospitalization rate, as well as a shorter length of stay with respect to usual care. Furthermore, the platform would lead to a reduction of 14.11% of rehabilitative hospitalization days, with a consequent increase in the overall accessibility to care (51.6%). From an economic perspective, considering 184,792 patients potentially treated with T-CUBE in Lombardy Region, an economic saving equal to 41% emerged on annual basis. With regard to T-CUBE acceptability, its intention to use is strictly dependent from its usefulness and ease of use perceived by the healthcare professionals involved, as well as by its capability to produce a relevant job and a high-quality output. In conclusion, T-CUBE represents an ideal strategic leverage useful to manage the current pandemic emergency, thus being a relevant example in which digital technologies gives the possibility to solve a health problem in an efficient and effective way.