The activation of persulfate using cold plasma and the synergy of plasma-generated reactive species and SO4•− in mineralization of organic dyes were assessed. In this regard, solutions of crystal violet (CV) as a triarylmethane dye and methyl orange (MO) as an azo dye, were treated with cold plasma, UV-C-activated sulfate radicals, and their combination. The achieved results showed 95% TOC removal, a synergy factor of 1.3 and an energy yield of 1.68 (g kWh−1) for the combined system. The contribution of oxidant species in CV (SO4•− > O2•- > •OH) and MO (SO4•−> O2•- >1O2) degradation was explored. Moreover, analysis of degradation products and density functional theory (DFT) calculations were adopted to find the degradation mechanism based on the minimum energy pathway. Experimental and DFT results revealed that while radical and nucleophilic pathways were the drivers of CV degradation, the electrophilic attack of oxidants was a more plausible mechanism for MO degradation. Additionally, a comparison of the results of different DFT methods with experimental values showed that the Kohn–Sham DFT yielded more accurate results compared to recommended double hybrid methods. Analysis of a treated real wastewater revealed that the background constituents had negligible effects on MO and CV degradation. The high TOC removal efficiency of the combined system suggests its feasibility for treating wastewater from fertilizer and pharmaceutical production facilities.