This study compares the effectiveness of seven redox-mediating compounds namely, 1-hydrozybenzotriazole (HBT), N-hydroxyphthalimide (HPI), 2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO), violuric acid (VA), syringaldehyde (SA), vanillin (VA), and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), which follow distinct oxidation pathways, for the degradation of trace organic contaminants (TrOCs). These redox-mediators were investigated for improved degradation of four TrOCs showing resistance to degradation by crude laccase from the white-rot fungus Pleurotus ostreatus. ABTS and VA achieved the highest degradation of the phenolic compounds (i.e., oxybenzone and pentachlorophenol), whereas the non-phenolic compounds (i.e., naproxen and atrazine) were best removed using VA or HBT. This implies that the non-phenolic compounds are more effectively removed by the radical species generated by the NOH type mediators (i.e., VA and HBT), while removal of the phenolic compounds may depend more on the stability and the redox potential of the radicals generated from the mediator, irrespective of the type. Notably, enzyme stability was greatly affected by the NOH type mediators but it was compensated by their rapid degradation capacity. Overall, VA and HBT (NOH type) appear to be the best mediators for enhanced degradation of the selected compounds without causing significant toxicity in the effluent.