Optimization of photocatalytic degradation of two natural estrogenic compounds, estrone (E1) and 17β-estradiol (17β-E2) in aqueous medium was performed on TiO2 coated Pilkington ActivTM self-cleaning glass as a novel approach to eliminate free nano-TiO2 releasing to the intended environment after treatment. The active glass was characterized by Atomic Force Microscopy (AFM), X-ray diffraction (XRD), and Raman spectroscopy to characterize the TiO2 nanoparticles. The main purposes were mineralization of target compounds in the treated water during the photocatalytic reaction and also to investigate the oxidation by products. Response Surface Methodology (RSM) has been applied to optimize the photocatalytic degradation by changing time, pH, and light intensity as effective factors. According to the results, time was the more effective parameter. The maximum efficiency degradation was achieved in alkaline media. Due to interactive effects between variable factors, 1 mg/L aqueous solution of E1 and 17β-E2 in water was totally decomposed by TiO2 photocatalyzed reactions under UV-C irradiation of 10.08 W/m2 for 52.49 min at pH 9.42. Results of GC-MS analysis were introduced 17-deoxy Estrone and 2-Hydroxyestradiol as intermediate products for E1 and 17β-E2, respectively. All of the peaks finally disappeared after 170 min. Optimized conditions were applied for real sample of wastewater, presenting 30.40% and 56.84% in the efficiency degradation of E1 and 17β-E2, respectively.