Ethylenediaminetetraacetic acid (EDTA) can form very stable complexes with heavy metal ions, greatly inhibiting conventional metal-removal technologies used in water treatment. Both the oxidation of EDTA and the reduction of metal ions in metal–EDTA systems via the microwave-enhanced Fenton reaction followed by hydroxide precipitation were investigated. The Cu(II)–Ni(II)–EDTA, Cu(II)–EDTA and Ni(II)–EDTA exhibited widely different decomplexation efficiencies under equivalent conditions. When the reaction reached equilibrium, the chemical oxygen demand was reduced by a microwave-enhanced Fenton reaction in different systems and the reduction order from high to low was Cu(II)–Ni(II)–EDTA ≈ Cu(II)–EDTA > Ni(II)–EDTA. The removal efficiencies of both Cu2+ and Ni2+ in Cu–Ni–EDTA wastewaters were much higher than those in a single heavy metal system. The degradation efficiency of EDTA in Cu–Ni–EDTA was lower than that in a single metal system. In the Cu–Ni–EDTA system, the microwave thermal degradation and the Fenton-like reaction created by Cu catalyzed H2O2 altered the EDTA degradation pathway and increased the pH of the wastewater system, conversely inhibiting residual EDTA degradation.