Abstract: Selective depression of pyrite remains a major bottleneck in copper flotation, particularly when high-pyrite ores are processed and saline water is used. In such environments, conventional approaches using lime and inert grinding media often fail to discriminate effectively between pyrite and valuable copper minerals due to strong copper activation on pyrite surfaces. This study introduced a novel approach using inorganic radicals generated from peroxymonosulfate (PMS) to selectively oxidize and depress pyrite. Flotation tests with synthetic high-pyrite ore blends showed that PMS significantly reduced pyrite recovery while maintaining or improving chalcopyrite flotation. Ethylenediaminetetraacetic acid (EDTA) extraction confirmed selective oxidation of pyrite, and electron paramagnetic resonance (EPR) spectroscopy identified hydroxyl (•OH) and sulfate ( \rm SO_4^\text • - ) radicals as the dominant reactive species. Iron ions from grinding media and mineral surfaces were identified as key activators of PMS. A major insight was pyrite’s dual role, acting both as a radical scavenger and an activator, which made it highly reactive and susceptible to radical-induced oxidation. This process converted surface copper–sulfur species into copper hydroxides, effectively suppressing pyrite flotation. While previous studies have applied EPR to detect radicals in simplified activator/precursor systems, this study provides the first direct mechanistic evidence of radical-driven selectivity in flotation by detecting inorganic radicals in a complex flotation slurry, thereby demonstrating their persistence under industrially relevant conditions and establishing a foundation for more effective and targeted flotation strategies.