The proposed investigation is aimed at providing useful suggestions and guidelines for the renovation of educational buildings, in order to do University classrooms safe and sustainable indoor places, with respect to the 2020 SARS-CoV-2 global pandemic. Classrooms and common spaces have to be thought again, for a new “in-presence” life, after the recent worldwide emergency following the spring 2020 pandemic diffusion of COVID-19. In this paper, starting from a real case study, and thus the architectural and technological refurbishment of an Italian University building (Campobasso, South Italy, cold climate), with the aims of improving the classrooms’ quality and safety, a comprehensive approach for the retrofit design is proposed. By taking into account the necessary come back to classrooms starting, hopefully, from the next months (Autumn 2020), experimental studies (monitoring and investigations of the current energy performances) are followed by the coupling of different numerical methods of investigations, and thus building performance simulations, under transient conditions of heat transfer, and computational fluid dynamics studies, to evidence criticalities and potentialities to designers involved in the re-thinking of indoor spaces hosting multiple persons, with quite high occupancy patterns. Both energy impacts, in terms of monthly and annual increase of energy demands due to higher mechanical ventilation, and indoor distribution of microclimatic parameters (i.e., temperature, airspeed, age of air) are here investigated, by proposing new scenarios and evidencing the usefulness of HVAC systems, equipment (e.g., sensible heat recovery, without flows’ contamination) and suitability of some strategies for the air distribution systems (ceiling squared and linear slot diffusers) compared to traditional ones.