Microwave (MW) irradiation is a promising alternative method for the treatment of sewage. In the present work, persulfate (PS) was effectively activated under microwave heating for p-nitrophenol (PNP) degradation in water. As a result, at a microwave power of 300 W, PS was successfully activated by microwave, resulting in a superior PNP degradation efficiency (96.8%) within 14 min. The specific microwave effect was explored from the perspectives of the PS utilization efficiency and the reaction activation energy in the PS+MW system, using a conventional heating system as the control. In addition, the effects of the initial pH, coexisting inorganic ions, and natural organic matter were evaluated, and the results showed that these three factors had negligible effects on PNP removal in the PS+MW system. Based on the results of the quenching experiment and electron paramagnetic resonance (EPR) detection, the major active radical was identified as SO4•–, while •OH played a small role during the oxidation process. The practical application of this system was examined, and it performed well in two water matrices: secondary treated wastewater (WW) and the Songhua River.