Heterogeneous photocatalysis has been increasingly investigated during the past years and has been recognized as a promising technique for clean and safe water purification. The current study exploits the advantage of this technique demonstrating that the removal of a biorefractory water pollutant named clofibric acid can be really improved by photocatalysis through a parametric comprehensive investigation and optimization study based on response surface methodology. Its novelty comes from the approach used to enhance the efficiency of the photocatalytic degradation of clofibric acid. A custom central composite design consisting of 49 trials was applied for process modeling and a quadratic robust model was derived based on the analysis of variance for the optimization of the process parameters. The effective removal of the target molecule with about 70% carbon mineralization was achieved under optimal photocatalytic conditions: 1.5 mg/L as the initial concentration of pollutant, 0.61 g/L catalyst, and an irradiation time of 190 min. Further, it was provided that nitrates play a positive role in the removal of this pollutant, while hydrogenocarbonates slow down its elimination. The ecotoxicity evaluation at different trophic levels confirmed the low toxicity of photodegradation by-products. Data analysis demonstrated that response surface methodology is a reliable approach for the optimization of the interactive effects of photocatalytic process parameters and is able to enhance their performance for the complete elimination of this hardly removed water pollutant.