In the present study, the degradation of amoxicillin trihydrate (AMT), using synthesized nanoscale zero-valent iron (nZVI) and bimetallic Fe and Ni nanoparticles stabilized with chitosan (Cs-Fe/Ni), in water was investigated. A central composite design combined with response surface methodology and optimization was utilized for maximizing the AMT reduction by the nanoparticles-water system. The importance of the various variables and their interactions were analyzed using analysis of variance and t-test. The effects of independent parameters were tested and the results showed that the initial concentration of AMT, pH, and nanoparticles dosage were all significant factors. Field-emission scanning electron microscopy images indicated that chitosan acts as a stabilizer preventing the agglomeration of nanoparticles. Also, chitosan and Ni increased the specific surface area of Cs-Fe/Ni. X-ray diffraction confirmed the existence of Fe(0) in fresh samples and the presence of Fe(II) and Fe(III) after the reaction with AMT. This study demonstrates that the nZVI technology could be a promising approach for antibiotic wastewater treatment.