The conventional froth flotation of fluorite from quartz-rich ores is reagent-intensive and faces selectivity challenges, impacting its economic and environmental sustainability. This study presents a novel green intensification strategy through the synergistic integration of nanobubble (NB) technology with Density Functional Theory (DFT) simulations. Systematic optimization of sodium oleate (collector) and sodium silicate (depressant) dosages in conjunction with hydrodynamic parameters (air/wash water velocity, NB generation rate) was conducted in both mechanical and column flotation systems. The incorporation of nanobubbles yielded transformative improvements: in mechanical flotation, collector and depressant consumption were reduced by over 50% while maintaining a concentrate grade exceeding 90% CaF₂ at 80% recovery; in column flotation, nanobubbles enhanced fluorite recovery by an absolute 7.2% at an equivalent high grade. DFT simulations elucidated the fundamental mechanisms, revealing strong, bidentate chemisorption of oleate onto fluorite surfaces and effective hydrophilic passivation of quartz by silicate. Crucially, the simulations demonstrated that nanobubbles reduce interfacial energy barriers and enhance local electrostatic attraction, thereby facilitating particle-bubble adhesion and stabilizing aggregates. This work establishes a sustainable processing paradigm where nanobubble technology, guided by fundamental surface science, enables simultaneous drastic reagent reduction and significant recovery intensification, offering a viable pathway for more efficient and environmentally benign fluorite beneficiation.