Building energy efficiency is strongly linked to the operations and control systems, together with the integrated performance of passive and active systems. In new high quality buildings in particular, where these two latter aspects have been already implemented at the design stage, users’ perspective, obtained through post-occupancy assessment, has to be considered to reduce whole energy requirement during service life. This research presents an innovative and low-cost methodology to reduce buildings’ energy requirements through post-occupancy assessment and optimization of energy operations using effective users’ attitudes and requirements as feedback. As a meaningful example, the proposed method is applied to a multipurpose building located in New York City, NY, USA, where real occupancy conditions are assessed. The effectiveness of the method is tested through dynamic simulations using a numerical model of the case study, calibrated through real monitoring data collected on the building. Results show that, for the chosen case study, the method provides optimized building energy operations which allow a reduction of primary energy requirements for HVAC, lighting, room-electricity, and auxiliary supply by about 21%. This paper shows that the proposed strategy represents an effective way to reduce buildings’ energy waste, in particular in those complex and high-efficiency buildings that are not performing as well as expected during the concept-design-commissioning stage, in particular due to the lack of feedback after the building handover.