Even though people spend the majority of their time indoors, the role of buildings in shaping human experience is still not well understood. The objective of this experimental project is to develop, test, and validate a data-driven neuroscience approach to understand the built environment’s impact on occupant cognitive function and mental health. The present study utilized virtual environments and electroencephalogram (EEG) and event-related potential (ERP) approaches, to provide objective neurophysiological information about how sustainable buildings (SBs) impact people’s affective and cognitive functioning differently compared to conventional building (CBs). The long-term goal is to assess the validity of sustainable building design protocols in promoting and increasing mental health and well-being and the mechanism used to accomplish these increases. The findings showed test subjects demonstrated increased visual system engagement and modulated attentional focus and control processing in the SB compared to the CB environments. The findings can be explained by the cognitive load theory, which is consistent with the interpretation of greater focus on the present environment and reduced internal mental processing (cf. mindfulness), based on the observed increased theta/delta activities and greater engagement of visual systems and corresponding decreases in frontal activity in the SB environment. In addition, the combination of virtual environment (VE) and EEG/ERP has the potential to advance design methods by soliciting occupants’ responses prior to completion of the projects. Building design is more than aesthetics; expanding the horizon for neuroscience would eventually result in a new knowledge base for building design, particularly sustainable building design, since the sustainability of the building often needs to be quantified.