The presence of antibiotics in water sources is a significant concern due to their potential environmental impact and the risks to human health. In the present research, Hierarchically Mesoporous UiO-66 (HP-UiO-66) with the high surface area (1011 m2/g) and large pore volume was synthesized using the reflux method on the liter scale. The successfully synthesis was confirmed by FT-IR, XRD, FESEM/EDS, N2-adsorption/desorption and zeta potential techniques. The HP-UiO-66 was utilized to remove two large structure antibiotics, chlortetracycline hydrochloride (CTC), and oxytetracycline (OTC). Box Behnken design was used to investigate the factors affecting the removal process and the interactions between them. The maximum adsorption capacities for OTC and CTC antibiotics were 252.9 mg/g and 234.2 mg/g at 35°C, respectively. The sum of normalized error method was applied to analysis of various error functions in the nonlinear fitting of equilibrium and kinetic data. The CTC and OTC adsorption kinetic followed fractal like pseudo second order model. The Langmuir isotherm fitted well to adsorption data. The results demonstrate that HP-UiO-66, can be used as recyclable and efficient adsorbents for large molecules antibiotics removal.