Future decarbonized and resilient energy systems will rely on significant demand-side flexibility resources to accommodate high penetration of intermittent renewable energy, particularly considering the rise in extreme weather events due to climate change. These resources must manage their load or generation, inevitably affecting end-user interests, such as comfort, productivity, and convenience. To address the supply-demand imbalance from a human-system interaction perspective, this study proposes “ergonomics in energy use,” a framework connecting the energy system to humans (i.e., energy users) through various flexibility resources, each characterized by a physical machine model, a target parameter, and a human evaluation model. The framework was demonstrated in an office building featuring three flexibility resources: an air-conditioning system, electric vehicles with smart chargers, and a lighting system. The framework was found to provide optimal operational strategies for these resources to minimize user dissatisfaction in various real-time load shedding and day-ahead scheduling programs. Based on the framework, we further present a novel method for demand flexibility quantification, defined as the maximum change in energy use for a given increment in service quality impact (using indices such as predicted percentage dissatisfied). This study shifts the perception of demand flexibility from a purely engineering concept to a social engineering concept, fostering human-centric energy system design, operation, and evaluation while paving the way for a new theory called “ergonomics in energy use.”