A high retention enzymatic bioreactor was developed by coupling membrane distillation with an enzymatic bioreactor (MD-EMBR) to investigate the degradation of 13 phenolic and 17 non-phenolic trace organic contaminants (TrOCs). TrOCs were effectively retained (90–99%) by the MD membrane. Furthermore, significant laccase-catalyzed degradation (80–99%) was achieved for 10 phenolic and 3 non-phenolic TrOCs that contain strong electron donating functional groups. For the remaining TrOCs, enzymatic degradation ranged from 40 to 65%. This is still higher than those reported for enzymatic bioreactors equipped with ultrafiltration membranes, which retained laccase but not the TrOCs. Addition of three redox-mediators, namely syringaldehyde (SA), violuric acid (VA) and 1-hydroxybenzotriazole (HBT), in the MD-EMBR significantly broadened the spectrum of efficiently degraded TrOCs. Among the tested redox-mediators, VA (0.5 mM) was the most efficient and versatile mediator for enhanced TrOC degradation. The final effluent (i.e., membrane permeate) toxicity was below the detection limit, although there was a mediator-specific increase in toxicity of the bioreactor media.