Tris-(2-chloroisopropyl) phosphate (TCPP), one of emerging organic pollutants has aroused a growing concern due to its potential biotoxicity and persistence. Oxidation degradation of using SO4*− based AOPs was explored. A pseudo-first order kinetics reaction with the degradation rate constant at 0.1789 min−1 fitted the transformation of TCPP. SO4*− was the predominant oxidation species confirmed by scavenging assay. Five steady intermediates including C6H13Cl2O4P (m/z 251.0002), C3H8ClO4P (m/z 174.9922), C9H17Cl2O5P (m/z 307.0266), C9H17Cl2O6P (m/z 323.0217), C6H12ClO6P (m/z 247.0134) were screened by high resolution mass spectroscopy analysis. The influences of vital parameters, i.e., natural anions, pH value, humic acid (HA) and peroxymonosulfate (PMS) dose were tested. HA and alkaline conditions can significantly decreased the photocatalytic rate to inhibit removal efficiency. EE/O evaluation had also proved that a neutral condition and HA pretreatment were conductive to elevating removal efficiency and reducing energy consumption. Based on proteomics and metabolic network analysis, TCPP was effectively detoxified as its further transformation proceeded, which was proved by nucleotide metabolisms, citric acid metabolism, oxidative phosphorylation and amino acid biosynthesis. To summarize, an appropriate degradation of TCPP likewise are effective for its detoxification, indicating the feasibility and security of TCPP elimination using UV/PMS treatment.