Blood Donation Supply Chain is a key component of any health care system. According to a recent study, the global need for blood was estimated to be 300 million units in 2017, while only 270 million units were collected. The COVID-19 pandemic has worsened the issue, and shortages have dramatically increased. For example, in Italy, the production of red blood cells in April 2020 was reduced by 36.4%, compared to that of 2019. Moreover, COVID-19 has stressed the need for delocalization of health services. In this light, we propose a novel paradigm for blood collection, which consists of collecting blood at donors’ homes rather than in donation centers, and it more comfortable and safe for patients, even in pandemic times. To manage home blood collection systems, we propose a decision support framework characterized by the integration between a Blood Donation Appointment Scheduling (BDAS) and a Multi-Trip Vehicle Routing Problem with Time Windows (MTVRP-TW). It consists of 3 planning phases: 1) possible time slots for donor appointments are created while balancing the production of the different blood types; 2) planned slots are turned into actual appointments based on the booking requests from donors; 3) a fleet of vehicles is organized to collect blood from donors’ homes at predefined donation day and time. The proposed framework has been tested and validated with the data of an Italian blood collection center.