The Cu(II)/HO system is recognized for its potential to degrade recalcitrant organic contaminants and inactivate microorganisms in wastewater. We investigated its unique dual oxidation strategy involving the selective oxidation of copper-complexing ligands and enhanced oxidation of nonchelated organic compounds. L-Histidine (His) and benzoic acid (BA) served as model compounds for basic biomolecular ligands and recalcitrant organic contaminants, respectively. In the presence of both His and BA, the Cu(II)/HO system rapidly degraded His complexed with copper ions within 30 s; however, BA degraded gradually with a 2.3-fold efficiency compared with that in the absence of His. The primary oxidant responsible was the trivalent copper ion [Cu(III)], not hydroxyl radical (OH), as evidenced by OH scavenging, hydroxylated BA isomer comparison with UV/HO (a OH generating system), electron paramagnetic resonance, and colorimetric Cu(III) detection via periodate complexation. Cu(III) selectively oxidized His owing to its strong chelation with copper ions, even in the presence of excess -butyl alcohol. This selectivity extended to other copper-complexing ligands, including L-asparagine and L-aspartic acid. The presence of His facilitated HO-mediated Cu(II) reduction and increased Cu(III) production, thereby enhancing the degradation of BA and pharmaceuticals. Thus, the Cu(II)/HO system is a promising option for dual-target oxidation in diverse applications.