Nowadays, pharmaceutical antibiotics are known as a serious class of pollutants. Therefore, it is important to develop effective methods for removing these pollutants from aqueous media. Different methods were applied for this purpose, and among these methods, chemical reduction by a cheap and eco-friendly nanocatalyst is the most efficient and simplest method. In this research, based on graphene oxide supported by zero-valent iron in mono-, bi-, and tri-metallic systems, various nanocomposites were synthesized and used to degrade tetracycline as a model antibiotic from aqueous media. An investigation was carried out on the synergic effect among graphene oxide and the nano zero-valent iron-based tri-metallic system as well as removal efficiencies. It was found that higher degradation efficiency is yielded by graphene oxide supported by Fe/Cu/Ag tri-metallic system. The maximum synergic effect occurs at an acidic medium. The Brunauer-Emmett-Teller, Fourier transform spectroscopy, scanning electron microscopy-energy dispersive X-ray analysis, transmission electron microscopy, and X-ray diffraction analysis were used to characterize the synthesized nanocomposites, which has successfully proved the loading of nanoscale Fe/Cu/Ag tri-metallic on a graphene oxide support. The central composite design was used to model and optimize all involved variables affecting antibiotic removal efficiency. The consequences illustrated the optimum condition regarding the removal of 50 ppm of tetracycline, for the nanocomposites dose of 3.0 mg ml −1 , the contact time of 30 min, and pH of 2, was achieved using the simplex non-linear optimization method. Moreover, antibiotic adsorption kinetic models were also investigated. Finally, the tetracycline removal from aqueous media at different concentrations, 25, 50, and 75 ppm, was successful by applying the proposed nanocomposite, and the results showed tetracycline removal efficiencies of above 70%.