Trimethoprim (TMP) is a pharmaceutical compound, which is commonly found in the water environment. The UV/chlorine process forms several reactive species, including hydroxyl radicals (HO•) and reactive chlorine species, to degrade contaminants. The influencing factors and the optimal operational conditions for the degradation of TMP by the UV/chlorine process were investigated. The degradation of TMP was much faster by the UV/chlorine process as compared to the UV alone or free chlorine alone process. A kinetic model was developed to simulate the degradation of TMP and determine the unknown rate constants. This study also predicted the relative contributions of each of the reactive species and photolysis using the developed kinetic model. It was found that the ClO• radical was the major reactant responsible for the degradation of TMP. Furthermore, the most important finding was the identification of the best operational conditions. The best operational conditions resulted in the lowest use of energy and electrical energy per order (EE/O), namely, (1) for the ultrapure water, the optimum intensity of the UV light and the free chlorine dosage were 2.56 Einstein/L·s and 0.064 mM, respectively, with a minimum EE/O of 0.136 kWh/m³; and (2) for the water matrix containing 3 mg/L NOM, the optimum intensity of the UV light and the free chlorine dosage were 3.45 Einstein/L s and 0.172 mM, respectively, with a minimum EE/O of 0.311 kWh/m³.