The revision of the Energy Performance Building Directive (EPBD 2024) introduced new requirements for the energy performance of both new and existing buildings aimed at achieving the 2050 decarbonization targets and at the same time ensuring an adequate level of indoor environmental quality (IEQ) by introducing mandatory monitoring of indoor air quality in non-residential buildings. This study deals with air systems and offers a comparative evaluation of the main methods used for defining and managing outdoor air flow rate values, comparing currently available calculation methodologies, including EN 16798–1, and introducing the hypothesis of recently developed optimized methods. Through the analysis of a case study concerning an office building supplied by a variable-flow primary air system equipped with terminal VAV boxes, the different design and control methods were applied and compared with the aim of identifying the differences in terms of supply flow rate values and in terms of indoor air quality. The results of the comparison show how the combination of different design methodologies and control strategies, influences not only the energy performance of the building but also the comfort and healthiness of the occupied spaces. The comparison also highlights the possible benefits of adopting optimized methods that, combined with the proper use of sensor-based control, allow satisfactory trade-offs between consumption and performance.