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Buildings are pivotal for grid flexibility under rising renewable penetration. However, unlocking these potential faces scalability bottlenecks and risks occupant comfort. This work proposes a scalable, human-centric framework using ubiquitous smart-meter data to assess and harness building demand flexibility. We develop non-intrusive, data-parsimonious, physics-informed machine learning methods for probabilistic occupancy inference, occupant-driven load flexibility quantification, and sensor-free indoor thermal modeling. These foundations culminate in a fast, multi-objective Pareto optimization framework that comprehensively evaluates energy-comfort trade-offs for flexible HVAC operation. This research bridges building energy dynamics, human behavior, and grid operations, paving the way for resilient, transparent, and occupant-engaged energy transitions.