To probe advantages in Fe-N-SiO2/TiO2 nanocomposite system, the visible photocatalytic degradation of the nonbiodegradable antibiotic oxytetracycline (OTC) by unsupported TiO2 and its modified composites by incorporating each of the Fe, N, and SiO2 dopants under a series of conditions were investigated. The structural and optical properties as well as the morphology of the prepared nanocomposites were also characterized applying Fourier transform infrared (FT-IR), X-ray diffraction, photoluminescence spectroscopy, UV-visible diffuse reflectance spectra and field emission scanning electron microscopy/Energy-dispersive X-ray spectroscopy (FESEM/EDX). In order to develop two models portraying appropriate functional relationships between two main responses (OTC removal efficiency and its specific removal rate (SRR)) and four numerical variables (OTC concentration, catalysis loading, initial pH and reaction time), two separate multivariate analysis pathways under response surface methodology (RSM) were taken. The results obtained all came down to the maximum SRR (220 OTC mg OTC removed/g cat. h) found at the maximum catalyst dosage of 1.5 g/l, and acidic pH of 3 after 0.5 h. Furthermore, the Fe-N-SiO2/TiO2 proved a stable photocatalytic activity during three subsequent reusability experiments, shedding light on its reliable potential for future application.