Water pollution by pharmaceuticals is currently a great concern due to their ecological risks. In this study, zirconium-based metal–organic frameworks (UiO-66-(COOH)₂) were used for removal of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac sodium (DCF). They have been synthesized using a hydrothermal method. Copper and iron metal ions were incorporated in the framework using post-synthetic modification techniques to produce UiO-66-(COOCu)₂ and UiO-66-(COOFe)₂. The resulted MOFs were characterized using X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), scanning/transmission electron microscopy, and Brunauer–Emmett–Teller. The effects of the pH, initial concentration, and adsorption time on the adsorption process of diclofenac were studied. The maximum adsorption capacities obtained on UiO-66-(COOH)₂, UiO-66-(COOCu)₂, and UiO-66-(COOFe)₂ were 480.5, 624.3, and 769.1 mg/g, respectively. The adsorption of diclofenac was found to be better fitted with Langmuir isotherm and pseudo-second-order kinetic models. The adsorption mechanism was investigated using XRD, FT-IR, density functional theory and Monte Carlo simulation, in which the latter method was used to calculate the adsorption energies and determine the possible interactions between diclofenac and the adsorbents. UiO-66-(COOH)₂, UiO-66-(COOCu)₂, and UiO-66-(COOFe)₂ exhibited good recyclability for diclofenac removal, which confirms the sustainability of these materials.