Chloroquine Phosphate (CP) is an antiviral drug used for treatment of COVID-19. It is released into wastewater and eventually contaminates natural water. This study reports an effective homogeneous catalysis way for CP degradation by the 2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO) enhanced persulfate (PDS) activation under UVB-LEDs irradiation at 305 nm. TEMPO at a low concentration (0.1 μM) enhanced CP degradation in UV/PDS process in deionized water at different pHs, in different anions and different molecular weight dissolved organic matter solutions and in real surface water. The enhancement was verified to be attributed to the electron shuttle role of TEMPO, which promoted the yield of SO by enhancing electron donating capacity of the reacting system. The degradation products of CP and their acute toxicities suggested that UV/PDS/TEMPO process has better performance on CP detoxification than UV/PDS process. This study provides a new way to tackle the challenge of pharmaceutical pollutions in homogeneous photocatalysis process for natural water and sewage restoration.