In this study, long-term performance of a persulfate (PS)-assisted direct contact membrane distillation (DCMD) process was examined for the treatment of secondary treated effluent spiked with a mixture of micropollutants including three pesticides and nine pharmaceuticals. A stand-alone DCMD (‘control’) was also operated under identical operating conditions for comparison. Depending on the micropollutant, the stand-alone DCMD achieved 86 to >99% removal. In comparison, removal by the PS-assisted DCMD was >99% for all investigated micropollutants. This was attributed to the fact that sulfate radicals (SO4–[rad]) formed following the activation of PS at the DCMD operating temperature (i.e., 40 °C) achieved micropollutant-specific degradation, which reduced the accumulation of micropollutants in the feed. Chemical structures of the micropollutants governed their degradation by PS. Effective degradation (>90%) was achieved for micropollutants that contain strong electron-donating functional groups (EDGs) in their molecules (e.g., amitriptyline and trimethoprim). Micropollutants containing both strong electron-withdrawing functional groups (EWGs) and EDGs in their molecules were moderately degraded (60–80%). In addition to the micropollutants, activated PS significantly degraded total organic carbon (70%) and total nitrogen (40%) from the secondary treated wastewater. This helped to reduce the fouling layer on the membrane-surface in the PS-assisted DCMD system. PS-addition appears to slightly increase the toxicity of wastewater, but with effective retention of PS and degradation products, DCMD permeate (i.e., treated effluent) was not toxic. This is the first study demonstrating the performance of the persulfate oxidation process in a continuous-flow membrane system for micropollutant removal and membrane fouling control.