Display omitted •Enhanced Cu-EDTA decomplexation is achieved in NTP coupled with PS system.•Heat, UV, Cu2+, and Cu-EDTA contributed to PS activation.•O2−, 1O2, OH, and SO4− contributed to Cu-EDTA decomplexation, especially for 1O2.•Synergistic mechanisms of Cu-EDTA decomplexation in this system are proposed. It is difficult to remove heavy metal–organic complex by conventional chemical precipitation. In this study, a novel strategy of coupling non-thermal plasma (NTP) and persulfate (PS) oxidation was developed for decomplexation of Cu-ethylenediaminetetraacetic acid (Cu-EDTA). An obvious synergistic effect between NTP and PS was achieved, resulting in 126% increase in reaction rate constant at 7 kV compared with single NTP system. PS was effectively activated by ultraviolet irradiation, heat, Cu-EDTA, and Cu2+ generated endogenously in NTP system. O2−, 1O2, OH, and SO4− contributed to Cu-EDTA decomplexation. Multiple spectroscopy analyses and Density Functional Theory calculation indicated that Cu–O and Cu–N of Cu-EDTA were destroyed. Finally, synergetic decomplexation pathways of Cu-EDTA in the NTP/PS system were proposed.